Immunogenetics of SLE and Primary Sjögren's syndrome

7

Immunogenetics of SLE and Primary Sj6gren's syndrome

Y. C. N G M. J. W A L P O R T

INHERITANCE VERSUS ENVIRONMENT

A role for genetic factors which predispose to the development of systemic lupus erythematosus (SLE) was first suggested by observations of familial cases. Approximately 5% of patients with SLE had a relative with the same disease (Estes and Christian, 1971). The results of studies of twins provided strong evidence for inherited factors. Monozygotic twins had 57% concordance for SLE, compared with a much lower rate in dizygotic twins, similar to that of other first degree relatives (Arnett and Shulman, 1975; Block et al, 1975, 1976). The observation that the concordance rate for SLE amongst monozygotic twins was 57%, rather than 100%, implicated environmental factors as determinants of expression of disease.

There is evidence in humans for heterogeneity of disease-susceptibility genes for the development of SLE. The majority of SLE patients are females of reproductive age, suggesting the involvement of sex hormones. However, families have been described amongst whom SLE showed a male inheritance pattern (Lahita et al, 1983b), similar to that of a murine lupus-prone strain, the BXSB mouse (described below). The strongest disease-susceptibility genes of all to be identified in humans are those encoding deficiencies of proteins of the classical pathway of complement, especially Clq, C2 and C4. Although patients with such complete, inherited deficiencies of complement proteins only account for a tiny minority of patients with SLE, their descrip- tion has stimulated detailed studies of complement proteins encoded within the major histocompatibility complex (MHC). These studies have led to the identification of null alleles (associated with no expressed protein) of one of the two isotypic variants of C4, C4A, as a putative disease-susceptibility gene present in the majority of patients with SLE. Possible physiological explanations for the association of complement deficiency with SLE are considered below.

The role of environmental factors was established by observations of a raised prevalence of serological abnormalities amongst spouses of SLE patients (DeHoratius and Messner, 1975; DeHoratius et a[,,1975; Lowen- stein and Rothfield, 1977) and amongst laboratory workers exposed to the

Bailli~re's ClinicalRheumatology--Vol. 2, No. 3, December 1988 623

624 Y . C . NG AND M. J. WALPORT

sera of patients with SLE (Carr et al, 1975; DeHoratius et al, 1979). The timing of the onset of disease within a given family also suggested a role for environmental factors: identical twins developed disease within a mean of two years of each other; siblings with a mean age difference of nine years developed disease within a mean of three years (Arnett and Schulman, 1976). SLE-like disease associated with drugs, such as hydralazine and procainamide, represent further examples of disease that is induced by exposure of a genetically-susceptible subject to an exogenous factor. Drug- induced SLE will be discussed separately.

The discovery of animal models of SLE allowed a direct experimental approach to the definition of genetic influences. The most striking feature of the results obtained from breeding experiments in mice with SLE-like disease is the great heterogeneity of disease susceptibility genes involved.

Primary Sj6gren's syndrome shares many of the immunological features of SLE, and indeed, there is a great deal of clinical overlap between the two syndromes. Fewer studies have been performed to define disease-susceptibility genes for the development of primary Sj6gren's syndrome than for SLE. This chapter concentrates on the genetic factors that contribute to the expression of SLE but where specific information for primary Sj6gren's syndrome is available, this is discussed.

PATHOGENETIC MECHANISMS

The presence in tissues of immune complexes is the most obvious patho- logical feature of SLE. In serum, the major abnormal finding is of extremely high titres of autoantibodies. Although current dogma is that the immune complexes in tissues result from the combination of these autoantibodies with autoantigens, this has not been proved unequivocally. Similarly, it is not certain what proportion of the immune complexes in tissues are deposited, preformed, from the circulation and what proportion form in situ (reviewed by Fournie, 1988).

Much experimental work in recent years has gone towards the detailed characterization of the antigens recognized by autoantibodies derived from patients with SLE and primary Sj6gren's syndrome. The common denomi- nator of most of the autoantibodies is that they bind to intracellular antigens which are nucleic acids and proteins involved in the transcription of DNA into RNA and the translation of RNA into protein. What are the mechanisms leading to the production of these autoantibodies in high titres?

Two broad hypotheses have been proposed to explain the development of these antibodies: (a) there is a primary failure of regulation of the immune response, allowing

the overproduction of 'forbidden' autoantibodies; and (b) autoantibodies arise as a normal immune response to the abnormal

presentation of autoantigen. For example, failure of the normal mechanisms for the elimination of immune complexes from the circulation might allow their deposition in many tissues, causing inflammation and release of autoantigens which stimulate an autoantibody

SLE AND SJOGREN'S SYNDROME 625

response (Lachmann and Walport, 1987). Arguments for and against each of these hypotheses are considered below.

MURINE MODELS

Genetic influences are readily demonstrable by breeding experiments in mice with SLE and these studies have been extensively reviewed (Theofilopoulos and Dixon, 1981, 1985; Steinberg et al, 1984). Some of the main points of interest are summarized:

1. Disease may be transmitted by transplantation of,bone marrow from lupus-prone strains of mice to their normal, irradiated counterparts. This shows that expression of the disease-susceptibility gene or genes within ceils arising from haemopoietic stem ceils is sufficient to induce disease.

2. There is marked genetic heterogeneity amongst the several strains of mice that develop lupus. Interbreeding experiments between mice of different lupus-prone strains, and between these and normal strains, have demonstrated that there are both dominant and recessive disease- susceptibility genes, and also protective genes which inhibit the development of disease, e.g. xid (see below).

3. In addition to disease-susceptibility genes, there are accelerating factors that hasten the onset of disease in lupus-prone animals. These may be either environmental or genetic. Viral (e.g. Gross virus or lymphocytic choriomeningitis virus) and bacterial infection may hasten the onset of disease. Of particular interest is lactate dehydrogenase (LDH) virus that inhibits disease development (Oldstone and Dixon, 1972); it has been discovered that this virus uses class II MHC molecules as its receptor (Inada and Mims, 1984; Mims, 1986) and thereby may enter and inhibit the activities of antigen presenting cells.

Disease-accelerating genes include: (a) those determining sex-hormone production in NZB/W mice; (b) a Y chromosome gene in the BXSB mouse; and (c) a gene that induces massive lymphadenopathy in MRL mice,

lymphoproliferation gene (lpr). 4. Recombinant inbred strains of mice have demonstrated the existence of

two types of genes determining expression of disease. Individual features of autoimmunity (e.g. anti-erythrocyte antibodies, anti-ssDNA antibodies, raised levels of IgM, thymocytotoxic antibodies) behave as though they are under the control of particular genes, some of which are linked to each other. These are separate from the 'background' genes encoding overall disease susceptibility.

5. There is no evidence that distinct allotypic variants of antibodies, T-cell receptors or autoantigens are involved in disease susceptibility. However, there is some evidence for selective usage of certain immunoglobulin V gene families in the formation of autoamibodies (Bona, 1988), although there is evidence that these gene families are present in

626 "/. C. NG A N D M. J . W A L P O R ]

normal as well as lupus-prone mice (Trepicchio et al, 1987). Similarly, there is evidence that a particular lineage of B lymphocytes bearing the Ly-1 antigen (CD5 in humans), may preferentially express autoantibodies (reviewed in Hayakawa and Hardy, 1988). These B-lymphocytes are usually expressed early in ontogenesis and are only present in small numbers in mature animals. In New Zealand mice, they are present in mature animals as a high proportion of circulating lymphocytes. The gene xid, which is associated with an immunodeficiency syndrome in normal mouse strains and with suppression of disease in lupus-prone strains, is found with normal numbers of Ly-1 + B cells when expressed in NZB mice. However, Ly-1 + B cells are expressed in normal numbers in MRL/1 mice, which develop an accelerated form of SLE. This observation casts doubt on a universally important role for Ly-1 + B cells in murine lupus.

6. The single abnormality of immune ceilular function common to all strains of lupus-prone mice is excessive activation of B-lymphocytes. It is not yet clear whether this is due to their excessive sensitivity to normally derived signals from lymphokines or whether they are stimulated excessively by abnormal production of lymphokines from other activated cells of the lymphon. In the case of the MRL strain of mice, the lpr, disease-accelerating, gene is associated with proliferation of T- lymphocytes of helper phenotype and it is tempting to believe that these accelerate disease by the excessive secretion of B-cell helper factors.

7. There is little evidence that inherited complement deficiency plays an important role in disease susceptibility to murine lupus, in contrast to the situation in humans.

8. The role of MHC-linked disease-susceptibility genes amongst inbred mice is less well established than amongst outbred humans. The various lupus-prone strains of mice do not share a particular MHC haplotype. A gene in, or linked to, the H-2 z haplotype of NZW mice, appears to be the dominant disease susceptibility gene in promoting high levels of anti- DNA antibodies and early nephritis in (NZB x NZW)F1 hybrids (Kotzin and Palmer, 1987).

It was recently reported that NZW and (NZB x NZW)F1 mice show impaired production of TNF-a (encoded within the MHC), and regular injections of TNF-a ameliorated nephritis and prolonged the life of these mice (Jacob and McDevitt, 1988). A restriction fragment length polymorphism of the TNF-a gene was characterized which was present in many lupus-prone mice, but also found in some normal strains.

IMMUNOGLOBULIN AND T-CELL RECEPTOR GENES

Analysis of the associations of genetic polymorphisms of these proteins with disease susceptibility is still at an early stage. The genetic organization of these proteins is complex. Each antibody heavy chain, encoded on chromosome 14, is derived from a variable region (V) gene, a diversity segment (D) gene, and a junctional segment (J) gene spliced with one of a series of


tandemly organized constant region genes (~t, 6, 73, 71, 72, y4, ~, c0. Light chains are encoded on 2 chromosomes--x on 2, )~ on 22--and are similarly derived by splicing of tandemly encoded V, J and constant genes. The T-cell receptor has a similarly complex organization. The opportunities for inherited variations to occur in the expression of these families of genes are therefore enormous. Most studies so far have concentrated on looking for associations between polymorphisms of the constant regions of these proteins and disease. Initial studies were of associations between SLE and immunoglobulin constant region allotypes defined serologically, Gm and Km allotypes. With the availability of cDNA probes for immunoglobulin and T-cell receptor genes, the results of studies of restriction fragment polymorphisms are starting to be reported. The majority of these so far have been negative or have only shown weak associations. However, these molecules are encoded within very large stretches of DNA (up to 4000 kb for the immunoglobulin heavy chain), and there is no evidence for crossover suppression within this DNA. Therefore, it is unlikely that study of the C region genes would give useful information about unlinked V genes encoding disease susceptibility.

With these comments in mind, four studies of Gm allotypes have been reported in SLE--two in Caucasian populations (Whittingham et al, 1983; Schur et al, 1985), one in an American black (Fedrick et al, 1983) and one in a Japanese population (Nakao et al, 1980). All found associations between SLE and particular Gm haplotypes, particularly when expressed in heterozygous combinations. However, no two studies gave the same results, although the differences may be explained by the different ethnic origins of the populations studied.

A single study of the prevalence of Gm and Km types in subjects with either anti-La or anti-RNP antibodies showed no associations with Gm type, but there was an increased prevalence, of the x-chain allotype, Km(1), amongst subjects with anti-La antibodies, of whom the majority had primary Sj6gren's syndrome (Whittingham et al, 1984).

The genetic origin of autoantibody-combining sites (i.e. V, D and J genes and their products) is currently the subject of much interest and falls outside the scope of this chapter. The review by Sanz and Capra (1988) summarizes present knowledge. There is, as yet, no evidence to support a role for genetic variation of the germline antibody repertoire as a disease-susceptibility factor in human disease.

Two studies have been reported examining the prevalence of restriction fragment length polymorphisms (RFLPs) of the T-cell receptor gene amongst patients with SLE. No associations were found between the gene frequency of T-cell receptor ~-, [3- (Fronek et al, 1986) and y-chain DNA polymorphic variants and SLE (Dunckley et al, 1988).

MHC

MHC in SLE

It is still not certain what is the relevant MHC gene(s), which confers

628 Y . c . NG AND M. J. WALPORT

increased susceptibility to the development of SLE despite the very large number of studies performed (reviewed in Walport et al, 1982). The two groups of genes encoded within the MHC, that have attracted the most interest, are the class II genes and the class III complement genes, particularly those encoding C4A, C4B (the two isotypes of C4) and C2. Initial studies of class II antigens showed a raised prevalence of HLA-DR2 and of HLA-DR3 amongst Caucasian SLE patients, though the relative risk of disease associated with possession of these antigens was only two- to threefold (reviewed in Walport et al, 1982). Subsequent studies confirmed a significant association between B8 and DR3 and SLE (Bell et al, 1984; Reveille et al, 1983).

Family studies demonstrated that the haplotype HLA-A1 B8 DR3 was more prevalent in SLE (Fielder et al, 1983). This haplotype is also associated with a number of other autoimmune diseases, e.g. Graves' disease, auto- allergic Addison's disease, juvenile diabetes mellitus, chronic active hepatitis and coeliac disease (reviewed by Batchelor and Welsh, 1982). Particular class II gene products are linked with many diseases associated with autoimmunity, e.g. HLA-DR4 with rheumatoid arthritis (RA) (see Chapter 5). One current hypothesis for the mechanism of such associations is that some class II molecules are particularly favourable restriction elements for the presentation of certain antigens to T-lymphocytes.

The second candidates within the MHC as disease-susceptibility genes for the development of SLE are the class III complement genes; the arguments in favour of these being relevant disease-susceptibility genes are considered below, and follow from the observed strong association of complete hereditary complement deficiencies with SLE.

It has recently been discovered that the genes for tumour necrosis factor-a and -~ are also encoded within the MHC (Spies et al, 1986). No polymorphisms of these genes or proteins have yet been encountered in humans, but inherited variation in TNF expression would represent another candidate for a disease-susceptibility gene for SLE, especially in view of the abnormal acute phase response in patients with SLE. The findings of reduced TNF-a production in (NZB x NZW)F1 mice (Jacob and McDevitt, 1988) (see above) are particularly intriguing in this respect.

MHC in Sj6gren's syndrome

Primary and secondary Sj6gren's syndrome with RA, each show different MHC associations (Moutsopoulos et al, 1979). An increased prevalence of the MHC antigens HLA-B8 (Gershwin et al, 1975; Fye et al, 1976; Chused et al, 1977; Moutsopoulos et al, 1979) and -DR3 (Chused et al, 1977; Moutsopoulos et al, 1979) is found amongst patients with primary Sj6gren's syndrome. In contrast, secondary Sj6gren's syndrome in association with RA is associated with HLA-DR4 (Moutsopoulos et al, 1979), and in particular with two haplotypes containing DR4:HLA-B44 DR4 (Powell et al, 1980) and HLA-B62 DR4 (Warlow et al, 1985).

Studies of possible associations of primary Sj6gren's syndrome with other MHC class II products have followed the detailed characterization of the


DR, DQ and DP loci. There is an increased prevalence of DRw52 (MT2), the product of the DR-J32 gene (which shows only limited structural polymorphism), amongst Caucasian and black patients with primary Sj6gren's syndrome (Wilson et al, 1984; Harley et al, 1986a), but a negative correlation was found between this product and disease amongst Japanese patients with primary Sj6gren's syndrome (Moriuchi et al, 1986). DRw52 is found in many haplotypes, especially those containing HLA-DR3, -5, -6 or -8, and it is therefore likely that disease associations with this product are secondary to associations with other class II molecules. A study of HLA-DQ products in primary Sj6gren's syndrome showed an increased prevalence of heterozygotes for HLA-DQ1/-DQ2 (Harley et al, 1986b). This finding has yet to be confirmed, but, if it is a true association, it suggests the possible importance of 'trans-associated' class II proteins, as seems likely in diabetes mellitus (Wolf et al, 1983).

Several groups have found strong correlations between the presence of HLA-B8 and HLA-DR3 and autoantibodies to Ro and La (Bell and Maddison, 1980; Manthorpe et al, 1982; Wilson et al, 1982). It has been suggested that there are ' immune response genes' in linkage disequilibrium with these MHC products related to the production of these particular autoantibodies (Bell and Maddison, 1980). However, a strong piece of evidence against this idea comes from studies of patients with inherited complement deficiencies by Meyer and collaborators (1985). They found that the most common autoantibody in patients with SLE associated with hereditary deficiencies of Clq, C2 or C4, was anti-Ro. There was no particular MHC haplotype associated with disease amongst these individuals, except in the case of C2 deficiency, which is predominantly inherited within the haplotype HLA- A10 B18 DR2. These observations exclude the hypothesis that there are specific MHC products encoding the anti-Ro antibody response. The study of Harley and co-workers (1986a) suggested an alternative role for the haplotype encoding HLA-B8 DR3 in influencing antibody responses to Ro and La. They found that levels of these autoantibodies were much higher amongst HLA-DR3-positive patients, but that their presence was not exclusively restricted to HLA-DR3-positive subjects.

Familial cases of primary Sj6gren's syndrome show similar characteristics to familial cases of SLE. In particular, serological abnormalities are found in apparently healthy relatives, and the occurrence of serological abnormalities is not HLA-linked within families (Boling et al, 1983; Reveille et al, 1984; Jabs et al, 1986).

SEX HORMONES

An important role for sex hormones in the development of human SLE is suggested by observations that the great majority of patients with SLE are female and that symptoms tend to develop around puberty and ameliorate after the menopause. Furthermore, SLE is sometimes exacerbated by oestrogen-containing oral contraceptives (Pimstone, 1966; Chapel and Burns, 1971; Garovich et al, 1980; Jungers et al, 1982). Lahita and his


colleagues have performed a number of studies showing abnormalities of the metabolism of sex hormones in patients with SLE. In particular, they have observed that SLE patients are hyperoestrogenic (Lahita et al, 1981) and have decreased serum concentrations of testosterone (Lahita et al, 1983a). These observations are consistent with the observed effects of sex hormones on the lupus-like illness of (NZB x NZW)F1 mice. Androgens protect these mice against disease whereas oestrogens accelerate the onset and severity of disease. A few patients with Klinefelter's syndrome and SLE have been described (reviewed in Lahita and Bradlow, 1987), and this concurrence would fit with the thesis that abnormal sex hormone profiles may predispose to the development of SLE. Ascertainment bias may result in the over- reporting of this association, compared with the true prevalence of Klinefelter's syndrome amongst all patients with SLE, which may not be in excess of that in the general population. A small number of human kindreds have also been observed in which SLE is found in multiple male family members (Lahita et al, 1983a). This may be the human counterpart of the BXSB mouse in which a Y chromosome gene, whose effects are not mediated by sex hormone levels, confers disease susceptibility.

MISCELLANEOUS PROTEINS

No linkage has been identified between a variety of polymorphic proteins and either SLE or primary Sj6gren's syndrome. For example, a study of the polymorphic variants of al-antitrypsin inhibitor, haptoglobin, transferrin and group-specific component, showed no deviation from normal phenotype frequencies amongst a group of patients with primary Sj6gren's syndrome (Mitchell et al, 1985).

GENETIC DEFICIENCY OF COMPLEMENT

The strongest disease-susceptibility genes for the development of SLE are inherited deficiencies in genes which code for one of the proteins of the classical pathway of complement, though patients with such deficiencies only account for a tiny minority of SLE cases. Review of the reported cases of genetic deficiency of each of the complement components (Schifferli et al, 1986a) demonstrates that the susceptibility is greatest for those with deficiency of Clq, Clr and Cls, and C4. Amongst these individuals the preva!ence of SLE is 88%. Subjects with deficiency of C2 or C3 respectively have a 68% and 79% incidence of immune complex disease. Since C4 and C2 are encoded within the MHC, it has been suggested that the association of SLE with deficiency of these components is due to genetic linkage with other immune response genes. This is very unlikely to be correct since there are several different MHC haplotypes found in patients with complete, inherited C4 deficiency (Meyer et al, 1985).

There are a number of arguments which suggest that the deficient complement protein is itself the predisposing factor to immune complex disease and

SLE AND SJ()GREN'S SYNDROME 631

these have recently been reviewed (Lachmann and Walport, 1987). The arguments can be summarized as follows:

1. SLE is found in association with inherited complement deficiencies encoded in different parts of the genome;

2. inherited complement deficiencies are hardly ever encountered amongst normal populations, excluding ascertainment artefact as the explanation for the association of deficiency with SLE; and

3. acquired complement deficiency states such as those which are associated with inherited C1 inhibitor deficiency and C3 nephritic factor are also associated with a raised prevalence of autoimmunity.

These observations suggest that there is a causal pathophysiological link between the complement deficiency and the development of SLE.

NULL ALLELES OF COMPLEMENT GENES ENCODED IN THE MHC

Because of the strong association of inherited homozygous complement deficiencies with SLE-like disease, several workers have studied the possibility of an association between SLE and partial inherited deficiencies of complement proteins. Glass and colleagues (1976) found an association between heterozygous C2 deficiency and rheumatic diseases, including SLE and juvenile chronic arthritis. There is an extensive polymorphism of both theC4A and the C4B genes which includes null genes (with no expressed protein, denoted by the symbol Q0, quantity 0). These null genes are moderately common amongst Caucasians with an overall prevalence of approximately 55% (30% with one or more AQ0 genes and 25% BQ0). Because of the association of complement deficiency with SLE, a number of groups have studied the prevalence of C4Q0 alleles amongst patients with SLE and documented amongst Caucasian patients, a markedly raised prevalence of C4AQ0 genes (Fielder et al, 1983; Christiansen et al, 1983; Reveille et al, 1985; Howard et al, 1986; Kemp et al, 1987), as shown in Tables 1 and 2. However, the majority of these C4AQ0 alleles were encoded on haplotypes bearing HLA-DR3 and the commonest haplotype was HLA-A1 B8 DR3 C4AQ0 C4B1 BfS C2-1 (Fielder et al, 1983; Reveille et al, 1985; Kemp et al, 1987). It was therefore impossible to disentangle the relative contributions of HLA-DR3 and of C4AQ0 to disease susceptibility, or indeed to exclude the possibility that a further disease-susceptibility gene was encoded within this haplotype.

Two approaches have been taken to identify the relevant disease- susceptibility gene or genes within the MHC. One has been to study the prevalence of C4 null alleles amongst Caucasian patients with SLE who do not carry HLA-DR3. A single such study showed an increased prevalence amongst these subjects of both C4AQ0 and of C4BQ0 alleles (Batchelor et al, 1987). The second approach has been to study the prevalence of C4 null alleles in non-Caucasian patients with SLE. The conse~us of studies on Black (Howard et al, 1986), Chinese (Dunckley et al, 1987; Hawkins et al,

632 Y.C. NG AND M. J. WALPORT

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634 Y . C . N G A N D M. J. W A L P O R T

1987) and Japanese patients with SLE (Dunckley et al, 1987) is that the prevalence of C4AQ0 alleles is increased and that these are not usually accompanied by HLA-DR3. However, not all groups have confirmed the raised prevalence of C4AQ0 alleles in patients with SLE (C. Alper, personal communication).

At first sight, it is not obvious how deficiency of only one of four expressed C4 genes is sufficient to increase disease susceptibility to SLE. C4 is an acute phase protein and its levels vary quite widely between different individuals. Several groups have found that it is impossible to ascertain whether a C4 null allele is present simply by measuring the C4 concentration in the subject's serum. The effects of null alleles on C4 concentration can only be clearly seen at a population level (Welsh et al, 1985), by correlating the mean C4 level with the number of expressed C4 genes.

There is a difference between the functional activities of the two C4 isotypes. The internal thiolester bond of C4A is more susceptible to nucleo- philic attack by amine groups, resulting in covalent amide bonds, whereas C4B is more susceptible to hydroxyl groups forming ester bonds (Isenman and Young, 1984; Law et al, 1984). Free amine groups are frequent in proteins whereas hydroxyl groups predominate in carbohydrates. C4B is haemolytically more active than C4A, presumably reflecting an abundance of cell surface carbohydrate residues. C4A is more active in binding to protein-containing immune complexes (Schifferli et al, 1986b). Since partial deficiency of C4A is much more strongly associated with SLE than a similar deficiency of C4B, the difference in binding specificities may give a further clue to the mechanism of this putative disease susceptibility gene.

MECHANISM OF THE ASSOCIATION OF COMPLEMENT DEFICIENCY WITH SLE

The pathogenesis of SLE appears to be mediated by immune complexes and complement which can be demonstrated in many organs by immunohisto- chemical techniques. The most striking serological abnormality in SLE is the presence of autoantibodies, reacting predominantly with nucleic acids and proteins concerned with nucleic acid transcription and translation. How might complement deficiency predispose to the development of these abnormalities? The classical pathway of complement interacts with immune complexes to prevent the formation of large, insoluble, lattices (reviewed by Schifferli et al, 1986a) and the covalent incorporation of C4b and C3b into the complexes allows binding of the complexes by cells bearing complement receptors. The net effect of these interactions is to enhance the efficiency of removal of immune complexes from the circulation by the fixed mononuclear phagocytic system. Complement deficiency might predispose to disease by not allowing the efficient removal and destruction of immune complexes from the circulation. Instead, these may deposit in many organs, causing tissue injury and the release of autoantigens, stimulating and perpetuating an autoantibody response (Lachmann and Walport, 1987) (Figure 1). An alternative explanation for the association of complement


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Figure 1. The effects of complement and CR1 on the handling of immune complexes in vivo. On the right of the figure is depicted the presumed physiological activities of complement and CR1 in the efficient clearance and proteolysis of immune complexes. On the left, the possible effects of deficiency of complement and/or CR1 are illustrated, leading to the establishment of an autoimmune response.

deficiency with SLE is that deficiency of complement may allow the establishment of chronic viral infections which stimulate autoantibody production. There is little experimental evidence to support the latter hypothesis. Deficiency of complement proteins is not associated with an increased expression of overt viral infection. Although complement has been shown in vitro to play a role in the lysis of cells infected with measles, there is no strong evidence to support such a role in vivo.

COMPLEMENT RECEPTOR TYPE 1 (CR1) AND IMMUNE COMPLEXES (IC)

There is evidence that CR1 on erythrocytes has a physiological role as a transport molecule for immune complexes within the circulation (reviewed by Hebert and Cosio, 1987). The ligands for CR1 are C3b, iC3b, C4b and iC4b. CR1 is distributed on many cell types, including myeloid cells, B lymphocytes, erythrocytes and glomerular podocytes. The majority of circulating cells carry CR1, and leukocytes bear up to 100 times more CR1 per cell than erythrocytes. However, the majority of CR1 in the circulation is located on erythrocytes because of the great numerical preponderance of erythrocytes over other cells bearing CR1. Medof and colleagues (1982) added immune complexes in vitro to whole blood and found that a large proportion of the complexes bound to erythrocyte CR1. Recently this binding reaction has been studied in vivo. Soluble IC injected into the aortas of baboons bound rapidly to circulating erythrocytes and were transported in this form to the fixed mononuclear phagocytic system (Cornacoff et al, 1983). Samples taken from catheters in the portal and hepatic veins showed that clearance of immune complexes from the circulation occurred during a single passage through the liver (Cornacoff et al, 1983).

This experimental system has given the opportunity to te~-the hypothesis


that defective complement function might interfere with the efficient clearance of immune complexes from the circulation by cells of the mononuclear phagocytic system. Immune complexes were cleared more rapidly from the circulation of decomplemented baboons than of normocomple- mentaemic baboons. These complexes were detected in tissues outside the fixed macrophage system, especially kidney and lung where they were presumably potentially able to cause damage (Waxman et al, 1984). In further experiments, binding to erythrocytes by IgA-containing immune complexes (poor classical pathway activators) was less efficient than by IgGl-containing immune complexes, and the IgA immune complexes were also detected in tissues outside the mononuclear phagocytic system (Waxman et al, 1986).

This experimental system has recently been transferred to humans (Schifferli et al, 1988a). Using tetanus-toxoid-anti-tetanus-toxoid immune complexes, it was shown that:

1. immune complexes bind to erythrocyte CR1 in vivo and that binding was proportional to erythrocyte CR1 number;

2. in some subjects, a proportion of the injected immune complexes were cleared from the circulation within the first minute after injection, before most of the complexes could have reached the hepatic circulation; and

3. this rapid clearance of immune complexes occurred mainly in subjects with low CR1 numbers, hypocomplementaemia, and low levels of binding of the immune complexes to the erythrocytes at one minute after injection (Schifferli et al, 1988b).

A further physiological role for CR1 is to function as a cofactor for factor I in the catabolism of bound C3b in two successive cleavages first to iC3b (Fearon, 1979; Iida and Nussenzweig, 1981) and then to C3dg (Medof et al, 1982; Ross et al, 1982; Medicus et al, 1983). Immune complexes bearing C3dg appear unable to activate complement further (Medof et al, 1982).

Reduced complement and CR1 activity may allow immune complexes to accumulate in tissues. Failure of cofactor activity of CR1 may also allow them to retain their phlogistic potential. Activation of the alternative pathway of complement and the activity of phagocytic cells may eventually allow elimination of immune complexes deposited in tissues but at the expense of considerable local damage. Furthermore, immune complexes found in tissues (whether deposited from the circulation or formed in situ) have the potential to be removed by lymphatics which will transport them to lymph nodes rather than the fixed macrophage system. In lymph nodes, such complexes have the potential to stimulate an antibody response, thereby perpetuating an antigen-driven antibody response (see Figure 1).

CR1 DEFICIENCY AND SLE---INHERITED OR ACQUIRED?

CR1 exhibits structural and numerical inherited polymorphisms (reviewed in Walport and Lachmann, 1988). These polymorphisms have been of great


interest because it was found that patients with SLE express reduced CR1 numbers on a variety of cell types, reviewed below. Because of this, the possibility was entertained that reduced CR1 expression might be under inherited control and might therefore constitute a disease-susceptibility gene for the development of SLE.

CR1 has recently been cloned, and this has allowed the detailed characterization of its inherited polymorphisms. The structural polymorphism is unusual because of the wide variation in molecular weight between the allotypic variants--160,190,220 and 250 kD (reviewed in Fearon, 1984; Ross and Medof, 1985). The molecular basis of this is variable duplication of the 60 amino acid repeating domain (SCR, short concensus repeat) that is the main structural element of CR1.

Even more unusual is the inherited polymorphism in the number of CR1 expressed per erythrocyte, which ranges from 100 to 1200 molecules per erythrocyte in the normal population. Levels of CR1 expression on erythrocytes from normal individuals were found to remain constant for prolonged periods (Brown and Broom, 1938). An early family study suggested that the level of expression of CR1 was an inherited trait controlled by two co- dominant alleles at an autosomal locus (Klopstock et al, 1965), a finding that was confirmed independently by Wilson and colleagues (1982). It has now been shown, using a cDNA probe for CR1, that there is an RFLP of the CR1 gene which correlates with numerical expression of CR1 in normal populations (Wilson et al, 1986a; Moldenhauer et al, 1987) (Figure 2).

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O O

7 .4kb 6 . 9 k b

Figure 2. Numbers of erythrocyte CR1 (CR1/E) in normal subjects (O) and in patients with systemic lupus erythematosus (0) grouped according to presence or absence of polymorphic bands at 6.9 kb and 7.4 kb on Southern blots, using HindIII and CR1.1, a 0.8 kb complementary DNA probe. Values are molecules per cell, and means are calculated from square-root- transformed data. Bars show 95% confidence limits. From Moldenhauer~e't al (1987), with permission.


There are two, allelic, HindIII fragments of 7.4 kb and 6.9 kb; individuals homozygous for the 7.4 kb and 6.9 kb patterns are high and low expressors respectively of CR1; heterozygotes show intermediate numbers of CR1. There is overlap between the homozygotes and heterozygotes in CR1 phenotype; because of this, it is impossible to ascertain a subject's genotype solely by examination of phenotype. There is evidence that additional inherited factors may affect CR1 numerical expression, since there is a two- to threefold range in CR1 numbers amongst homozygotes for the 7.4 kb allele, and this variation is stable amongst normal individuals.

Amongst patients with SLE, there is a significant decrease in the number of CR1 on erythrocytes (Miyakawa et al, 1981; Iida et al, 1982; Wilson et al, 1982; Taylor et al, 1983; Minota et al, 1984; Ross et al, 1984; Walport et al, 1985), B-lymphocytes and polymorphs (Wilson et al, 1986b). It has been the subject of considerable controversy as to whether this decrease is predominantly acquired or inherited (reviewed in Wilson et al, 1987a; Walport and Lachmann, 1988).

Evidence for a role for inherited factors came from family studies of Miyakawa and colleagues (1981) in Japan and from Wilson and co-workers (1982) in Boston who found that relatives as well as patients had decreased erythrocyte CR1 numbers. In contrast, Watport and colleagues (1985) found in an English population that whilst patients with SLE had decreased erythrocyte CR1, their relatives did not. The findings by each of these groups have in each case been subsequently supported by the distribution of the HindlII polymorphism using the same CR1 cDNA probe (Wilson et al, 1987b; Moldenhauer et al, 1987). The reasons for this discrepancy are unclear; however, Wilson and colleagues (1987a) have subsequently performed a family study of SLE patients and controls in Athens and confirmed Walport's findings of normal CR1 expression in relatives of SLE, whilst the patients had decreased expression. Wilson and colleagues (1987a) noted that the mean number of CR1 in the normal population was signifi- cantly lower in Athens than in Boston. These findings suggest differences in the geographical expression of the CR1 numerical polymorphism.

There are several lines of evidence to support the idea that the low numbers of CR1 seen amongst patients with SLE are acquired (reviewed in Walport and Lachmann, 1988.

1. There are correlations between indices of complement activation and CR1 numbers amongst patients with SLE (Iida et al, 1982; Ross et al, 1984).

2. Within each numerical genotype of CR1 (defined by the HindlII RFLP) SLE patients showed lower CR1 numbers than normal subjects (Moldenhauer et al, 1987) (see Figure 2).

3. CR1 loss in the circulation in vivo was found from erythrocytes transfused into patients with active SLE (Walport et al, 1987).

4. Autoantibodies to CR1 have been found in a very few patients with SLE, though these were not present in the majority of SLE patients with low CR1 numbers (Wilson et al, 1985; Cook et al, 1986).

5. Low CR1 numbers on erythrocytes of patients with a variety of diseases


have now been described, including autoimmune haemolytic anaemias, paroxysmal nocturnal haemoglobinuria, AIDS and lepromatous leprosy (reviewed in Walport and Lachmann, 1988).

Whether inherited or acquired, the reduction in CR1 numbers on erythrocytes of SLE patients may impair the physiological mechanisms for the clearance of immune complexes from the circulation and allow deposition of these in other organs, promoting a vicious cycle of inflammation and antigen-driven autoantibody production (Lachmann and Walport, 1987).

DEFECTS IN THE FIXED MACROPHAGE SYSTEM

It follows from the above remarks that failure of the mononuclear phagocytic system itself would promote inflammation in a similar fashion to complement or CR1 deficiency by impairing the normal removal of immune complexes from the circulation. Many studies of the function of the mononuclear phagocytic system in human diseases have been performed following observations (Haakenstaad and Mannik, 1974) that the reticuloendothelial system of experimental animals could become 'saturated' in the presence of high levels of circulating immune complexes.

Function of the fixed macrophage system in humans has been studied by measuring the clearance kinetics of injected autologous erythrocytes modified by opsonization with antibody or complement, or damaged by heating for a short time at 49.5~

There is some evidence for genetic variation amongst normal subjects in the rate of clearance of autologous IgG-coated erythrocytes by the spleen. This rate was decreased amongst normal subjects with the HLA-B8 DR3 haplotype (Lawley et al, 1981; Kimberley et al, 1983) and also in normal subjects carrying HLA-DR2 (Kimberley et al, 1983). In the latter study, abnormal phagocytic function of peripheral blood monocytes from subjects with HLA-DR2 was also demonstrated. A reduction in the rate of clearance of IgG-coated erythrocytes has also been described in patients with SLE (Frank et al, 1979, Hamburger et al, 1982; Lockwood et al, 1979), which correlated in some studies with indices of disease activity (reviewed in Frank et al, 1983).

IgG-coated erythrocytes are cleared from the circulation mainly in the spleen, whereas soluble immune complexes are removed predominantly by the mononuclear phagocytic system of the liver. The relevance of abnormalities in the clearance of opsonized erythrocytes from the circulation to possible abnormalities in the clearance of soluble immune complexes is uncertain. The availability of soluble immune complexes (Schifferli et al, 1988a,b) and heat-aggregated IgG (Lobatto et al, 1987) as probes of the mononuclear phagocytic system in humans will allow re-examination of the concept of 'reticuloendothelial blockade' in diseases mediated by immune complexes.


DRUG-INDUCED SLE

Drugs such as hydralazine, procainamide and isoniazid may be associated with the appearance of a syndrome similar to SLE. A clear relationship with the exogenous insult exists since the syndrome is reversible on withdrawal of the drug (Perry, 1973). There is evidence for disease-susceptibility genes for SLE induced by hydralazine and procainamide. There is a significant increase in frequency of subjects with slow acetylator status; of a total of 109 patients with SLE associated with hydralazine reported, 90 were slow acetylators (Perry, 1973; Strandberg et al, 1976; Mansilla-Tinoco et al, 1982; Russell et al, 1987). A similar association has been described for procainamide-induced disease (Woosley et al, 1978). Slow acetylation is inherited as an autosomal recessive trait (Evans, 1968). There is also an association of hydralazine- induced lupus with HLA-DR4 (Batchelor et al, 1980; Russell et al, 1987), though in one series, this association was not confirmed (Brand et al, 1984). There is a marked preponderance of females in this disease, similar to idiopathic SLE.

A role for complement has been adduced for hydralazine-induced lupus. In vitro, using purified complement components, hydralazine has been shown to inactivate C4, especially C4A, and it has been suggested that this may be important in pathogenesis (Sim et al, 1984; Sire and Law, 1985). There are weaknesses in this proposition--notably that the MHC association is different from idiopathic SLE (HLA-DR4 (Batchelor et al, 1980)), that no in vivo or 'in whole serum' effect of hydralazine on complement has been shown so far, that drug-induced SLE is associated with a rather different spectrum of autoantibodies compared with its idiopathic counterpart (autoantibodies to histones are dominant and anti-DNA antibodies have only rarely been described in drug-induced lupus). If hydralazine promoted the development of SLE by the 'complement route', it would be predicted that the MHC complement disease-susceptibility genes would be the same as for idiopathic SLE and that the resulting autoantibodies would have a similar spectrum of reactivity. These predictions do not accord with the data.

SLE AND ACETYLATOR AND HYDROXYLATOR PHENOTYPES

In contrast with SLE induced by drugs, several groups have found no evidence for any alteration in the prevalence of slow acetylators amongst patients with idiopathic SLE (reviewed in Baer et al, 1986a). There is a single report (Baer et al, 1986b) of an increase in the prevalence of 'poor hydroxylators' of debrisoquine (catalysed by a cytochrome P450 enzyme) amongst Caucasian patients with SLE.

SLE AND OTHER DISEASES

Chronic granulomatous disease

A rash resembling discoid lupus erythematosus has been described in the

SLE AND SJ()GREN'S SYNDROME 641

female carriers of X-linked chronic granulomatous disease which is sometimes associated with systemic manifestations, including oral aphthous ulceration, photosensitivity and, rarely, Raynaud's phenomenon and pleurisy (Schaller, 1972; Brandrup et al, 1981). A similar syndrome has also been described in two siblings with an autosomal form of the disease (Stalder et al, 1986), suggesting that defective oxidative metabolism itself is the susceptibility factor associated with the development of this syndrome. However, no consistent immunological abnormalities have been found; in particular, the lupus-band test is negative in the discoid-like lesions, and no autoantibodies are found (Schaller, 1972). The relationship of this syndrome to SLE must therefore be questioned.

Porphyria

Approximately 25 patients with coexisting porphyria and SLE have been reported (reviewed in Rosemarin et al, 1982). No causal relationship has been established between these two diseases. Immunoglobulin and complement deposits are commonly seen around dermal blood vessels and at the dermoepidermal junction of patients with porphyria cutanea tarda (Epstein et al, 1973). However, these abnormalities are mainly restricted to light- exposed skin, and in the study of Epstein and colleagues (1973), no autoantibodies were seen in the majority of patients studied.

SUMMARY

SLE is a syndrome defined by clinical criteria and by the presence of autoantibodies reactive with nucleic acids and proteins concerned with transcription and translation. Breeding experiments in mice have illustrated the enormous genetic heterogeneity of this syndrome, of which the final common pathway is a widespread immune complex disease. The causes of SLE in humans are likely to be equally multifactorial. Family studies have demonstrated that genetic factors exist, but each factor appears to be a relatively weak disease-susceptibility gene. The major exceptions to this are the very rare complete deficiencies of classical pathway complement components, which are almost invariably accompanied by the development of SLE. Observations of these patients have led to the formulation of hypotheses relating complement and its receptor, CR1, to the defective removal of immune complexes from the circulation.

Acknowledgements

The authors' experimental work described in this chapter was supported by grants from the Arthritis and Rheumatism Council and the MRC.

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Immunogenetics of SLE and Primary Sjögren's syndrome

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