Rheumatoid
arthritis
Paul Wordsworth John
Rheumatoid
arthritis
which the abnormal agent(s) but progress been unrevealing. is slowly association
Radcliffe
is often considered immunological towards
In contrast,
becoming
Hospital,
clearer.
identifying
such
In particular,
extrinsic
Opinion
disease in
by an infectious
factors
has so far
of host susceptibility
the nature
of the HLA
class
II
into its pathogenesis
novel forms of therapy.
in immunology
Introduction arthritis (RQ is one of the commonest autoimmune diseases with a life-time incidence approaching 1 per cent in most populations worldwide, although there are some important exceptions to this. In common with many of these complex multifactorial disorders, such as type I diabetes mellitus and coeliac disease, there is emerging evidence to suggest that susceptibility to RA is determined by several genes [lo]. In this review I shall focus mainly on the genetic component of this disease, which can be divided into two parts-one part is associated with genes within the MHC and the other with genes outside the MHC. Despite the slow progress in identifying possible trigger factors [2*,3*], it is salutary to realize that the genetic component is probably relatively small since concordance rates in monozygotic twins are no more than 30 per cent and may be as low as 12 per cent [l-l. However, such twin studies can only give a very rough guide to the relative importance of genetic and non-genetic influences since they are beset both by problems of ascertainment bias and the potentially long delay (up to 40 years) which may occur before the second twin develops the disease . Furthermore, it is still not entirely clear whether the genetic factors are primarily important in determining the outcome of the disease rather than the initial susceptibility to synovitis, which may be self-limiting. As the locus within the MHC most closely associated with RA has been more precisely defined it has, at least, become somewhat easier to determine the full extent and nature of its contribution to the disease. Rheumatoid
Long-range
is triggered
with the disease has led to new insights
Current
UK
to be an autoimmune
response
the genetic component
and possible
susceptibility
Oxford,
1992, 4:76&769
identical HLA haplotypes, show a significant distortion from the expected random pattern of sharing [1*,4**]. Second, studies in outbred populations of most ethnic groups reveal associations with specific HIA markers, in particular with the class II antigen, DR4, in the majority of populations [ 5.1, These results indicate that genes linked to HLA must be involved, but does not prove that these genes themselves are necessarily of primary importance. However, since the associations with MHC class II markers are almost universally stronger than with class I, the area of interest must lie towards the centromeric end of the MHC, probably in the class II subregion. Nevertheless, the density of genes within the MHC (probably well over 100) still represents a considerable obstacle to the precise identification of the HLAlinked locus (or loci) involved in RA [6]. Considerable spice has been given to this search by the discovery of several loci within this region of the MHC that have potentially very important immunological functions. These include tumour necrosis factor (TNF)-CLand -p, heat shock protein 70, a number of complement proteins and, more recently, several loci located between the genes HLADP and -DQ, which encode proteins that play an important role in the cytosolit processing and transmembrane transport of antigens [7*]. Furthermore, it has been demonstrated by pulsefield gel electrophoresis that there is an apparent 100 000 nucleotide base pair inclusion between DR and DQ on all DR4 haplotypes relative to all other haplotypes; this could contain transcripts relevant to the development of RA [8] The association with HLADR4 could be equally well explained either by the direct involvement of DR4 or a tightly linked gene.
mapping of HLA-linked Fine mapping of HLA-linked
genes
susceptibility
genes Two parallel lines of investigation have clearly indicated a central role for genes within the MHC in the aetiology of RA. First, studies of siblings with RA, who have
Most DR haplotypes can be distinguished by their different DNA restriction fragment length polymorphisms,
Abbreviations AIDSacquired immune deficiency syndrome; ELAM--endothelial leukocyte adhesion molecule; HI_-human leukocyte-associated antigen; MHC-major histocompatibility complex; PCR-polymerase chain reaction; RA-rheumatoid arthritis; TN&tumour necrosis factor. 766
@
Current
Biology
Ltd ISSN
0925-7915
Rheumatoid
revealed by probes at the DR and DQ loci. However, this is not the case for the various subtypes of DR4 (of which there are at least 14 currently recognized). This indicates that there is a very high degree of conservation of the DNA on all DR4 haplotypes [9]. If there is differential susceptibility to RA associated with the various DR4 subtypes, it is most likely to be arising from the DRBl gene rather than from other genes in the flanking DNA, as polymorphism within this gene is responsible for generating the various DR4 subtypes [lo]. Several studies in caucasoids have now established that there is indeed a differential association of the disease with the DR4 subtypes [ 1l-131, thereby pinpointing DICE31as the primary locus responsible for RA within the HIA class II region. In addition to the positive associations with the DR4 subtypes, Dw4, Dw14 and Dw15, there are also associations with DRl in many populations, DRwlO in some and DRGDwl6 in the Yakima American Indians [ 141. Attempts to understand these apparently disparate associations have led to the development of the ‘shared epitope’ hypothesis of susceptibility. All these HL.4 molecules that are positively associated with susceptibility to RA share a high degree of amino acid sequence homology in the third allelic hypervariable region of the DRB-chain, which constitutes one side of the antigen-binding site. In particular, charged amino acid substitutions at positions 71 (DwlO) or 74 (Dw13), where the side chain is believed to point towards the binding site, abolish susceptibility to RA [12].
HLA-DR4: susceptibility
or severity
marker?
Even in populations in which there has not been a clear strong association of RA with a single HLA class II allele - such as Israeli Jews and Greeks-it is now clear that a combination of those alleles, bearing the shared susceptibility epitope is associated with a significant risk of RA [ 15*,16*]. However, it is possible that in these ethnic groups the disease may be somewhat milder than in populations where Dw4 predominates, such as in northem Europe (H Moutsopoulos, personal communication). This may also be the case in Chinese patients where the predominant DR4 subtypes associated with the disease are Dw14 and Dw15 [17*]. Further evidence of an influence of HLA on the severity of the disease has come from studies of the Felty syndrome and relatively severe forms of erosive rheumatoid arthritis [ 18**,19°,20*]. First, it is clear that the Felty syndrome has an almost complete association with Dw4 [ 18**]. Second, more severe forms of RA are significantly associated with genotypes that contain the Dw4/Dw14 and Dw4/DRl alleles [ 18**,19*]. This observation has also been made from the pooled data from a number of previous studies and has led to the suggestion that the susceptibility linked to HL4 might be recessive in nature [4**]. Finally, a long-term follow up of multiple case families has determined that the expected risk of recurrence in the immediate relatives of probands developing the disease is related in part to HLA-linked genes and in part to other genetic factors [ 21.1.
How can we interpret
arthritis
Wordsworth
the HLA associations
of
RA? The strong HLA associations of RA appear to place antigen presentation to CD4+ T cells at the heart of the pathological processes involved. It is not difficult to envisage a restricted range of potentially arthritogenic peptides capable of binding to a limited array of HLA molecules with certain shared physicochemical characteristics. How ever, it is equally possible that this interaction is im portant at an earlier stage of T-cell ontogeny-namely, during the positive and negative selection of the T-cell repertoire in the thymus. In contrast, the possibility that there may be autoimmune responses (perhaps by molecular mimicry with some foreign antigen) directed against those DRB molecules associated with inflammatory arthritis seems to have been ruled out, at least in certain animal models [22-l.
Several studies have now examined the possibility that there may be a restricted usage of antigen receptor by T cells within the rheumatoid joint. Considerable interest was provoked by reports of preferential usage of the VP14 segment by synovial lymphocytes, raising the possibility of a superantigen effect, perhaps in response to an intra-articular pathogen [23*]. These results have not gained wide acceptance as yet and there is no really strong evidence to support the idea that there is clonetypic predominance in the intraarticular T-cell response in RA [24*-27-l. Of course, it is possible that activated lymphocytes could trafic to the synovium subsequent to activation at sites away from the joint. While this question has not been directly addressed for ‘I’cells, one recent paper has raised the intriguing possibility that the traf ficking of neutrophils to the inflamed synovium might be influenced by down-regulation of endothelial leukocyte adhesion molecule (ELAM)-1 expression by the adminis tration of sodium aurothiomalate [2x*]
Non-HLA
factors in RA
No account of RA would be complete without mention ing the role of rheumatoid factors and this 11~1sbeen IC cently reviewed [29-,30-l, It is of ~~~rticular interest that the presence of rheumatoid factor often seeni~ kJ prc date the development of the disease by man!. )cars [3 1. ! however, it cannot be regarded as a very specific Indicz tor of subsequent disease. Likewise, a full explanation for the widespread glycosylation defect which affects the Fc portion of IgG (the &and for rheumatoid factors) as well as many other biologically important molecules remam~ tantalizing but elusive [32*]. In addition, it ha.+ also been reported that an impaired ability to oxidize sulphur-containing compounds, such as S-~drbo~methylil-L-cl;steint-, is associated with RA. This may be a useful predictor of those patients seen in an early synovitis clinic who are likely to go on to progressive disease [ 33* 1.
767
768
Autoimmunitv
Potential
novel therapies
For the immediate future, therapies aimed at blocking some component of the ternary complex (HLA molecule-antigen-T-cell receptor), which is believed to be involved in the pathogenesis of RA, remain entirely speculative. However, a number of trials have been initiated with murine or chimeric anti-CD4 antibodies that it is hoped might influence the disease process by an action on CD4+ T cells [34-,35*]. For a while there was anecdotal evidence that the depletion of T cells, consequent on the development of acquired immune deficiency syn drome (AIDS), was associated with the amelioration of RA. However, a recent report of a patient with AIDS and RA, whose active synovitis did not improve, perhaps casts some doubts on this hypothesis [36-l.
5. .
WORDSWORTHBP, BELLJI: The Immunogenetics
of Rheumatoid Arthritis. Springer Seminars in Immunopatbology 1992, 14159-78. A useful review of the association of various HIA allels with RA in a variety of different ethnic groups. 6.
SARGENT CA, D~JNHAM I, CAMPBELL RD: Identification of Multiple HTF-island Associated Genes in the Human Major Histocompatability Complex Class III region. !24BO J 1989, 8:2305-2312.
BP, SALMON M: The HLA Class II Component of Susceptibility to Rheumatoid Arthritis. Buifliere’s Clin Rheumatol 1992, 6~325-336. This review introduces the possibility thar HLADR alleles may be the most relevant in determining persistence of joint disease rather than the Initial susceptibility to synovitis. 7. .
WOKUSWORTH
8.
D~JNHAMI, SARGENTCA, DA~KINS RL, CAMPBELLRD: An Anal-
ysis of Variation in the Long-range Genomic Organization of the Human Major Histocompatibility Complex Class II Region by Pulsed-field Gel Electrophoresis. Genomicr 1989, 5~787-796.
Conclusions Considerable progress has been made in the past year in elucidating and confirming the nature of the HLA class II association with RA. It is now recognized that HIADR4 is a marker for more aggressive forms of the disease and that particular combinations of susceptibility alleles (e.g. ~w4/~wl4) are associated with more severe forms of the disease, such as the Felty syndrome. Unfortunately, this has not yet been translated to any successful form of therapy, which may not be surprising since the HIAlinked component of the disease probably accounts for no more than 10 per cent of the whole. Meanwhile the search continues for the elusive pathogens that many believe underlie the triggering of the disease. References
and recommended
Papers of particular
interest, published
within the annual period of re-
1. WORDSWOR~-~ BP, BEU JI: Polygenic Susceptibility in . Rheumatoid Arthritis. Ann Rheum Dis 1991, 50:343-346. A comprehensive review of the relative importance of genetic and nongenetic factors in RA.
BURMESTER GR: Hit and Run or Permanent Hit? Is There Evidence for a Microbiological Cause for Rheumatoid Arthritis? J Rbeumatol 1991, l&1443-1445. A challenging review of the possible role of microorganisms in the pathogenesis of RA, including a summary of the various organisms that have been invoked. 2. .
3. SIU~ANAJ: Is Rheumatoid Arthritis and Infectious Disease? . Br Med J 1991, 303:20&201. A somewhat sombre view, but this is a useful review of progress so far towards identifying any infectious triggers in R4 suggesting that new leads are required. ..
NICKL~~ JA, NOREEN HT, SE%ALLM, BACH FM: Southern AnaIysis of DNA Polymorphism among Dw Subtypes of DR4. Hum Immunol 1985, 13:95-103.
10.
GREGER~ENPK, SHEN M, SONG QL, MERRYMANP, DEGARS, SEKI
I, MACJ: Molecular Diversity of HLA-DR4 Haplotypes. Proc Nut1 Acud Sci USA 1986, 83~2642-2646. 11.
RIGBY AS, SILMAN AJ, VOEU~ L, GREC~RY JC, OLLIER WER, KHAN MA, NEPOM GT, THOMSON G: Investigating the HLA
Component In Rheumatoid Arthritis. An Additive (Dominant) Mode of Inheritance is Rejected, a Recessive Model is Preferred. Genetic Epidemiol 1991, 8:153_175. This is a reallygoodread with plenty of references and a comprehensive review of many of the largest population and family studies reported in the world literature. The authors claim that analysis of HIA haplotype sharing between a&ted sibling pairs is more in keeping with a recessive rather than a dominant mode of inheritance of susceptibility at this locus.
NE~OM GT, BYERSP, SEYFWEDC, HEALEYIA, WILSKIEKR, STAGE D, NEPOM BS: HLA Genes Associated with Rheumatoid
Arthritis. Identification of Susceptibility AlIeles Using Specific Oligonucleotide Probes. Arthritis Rbeum 1989, 32:15-21. 12.
WORDSWORTHBP, IANCHBURYJSS, SAKKASLI, WEISH KI, PANAYI
GS, BELLJI: HLA-DR4 Subtype Frequencies in Rheumatoid Arthritis Indicate that DRF3I is the Major Susceptibility Locus Within the HLA Class II Region. Proc Nat1 Acad Sci USA 1989, 86:1004~10053. 13.
GAO XJ, OLSEN NJ, PINCUS T, STASH-NY P: HLA-DR AlIeles with Naturally Occurring Amino Acid Substitutions and Risk for Development of Rheumatoid Arthritis. Arthritis Rbeum 1990, 33:93%946.
14. .
WILKENS RF, NEPOM GT, MARKS J, NETTLES JW, NEPOM BS:
reading
view, have been highlighted as: . of special interest .. of outstanding interest
4.
9.
Association of HLA-Dw16 with RA in Yakima Indians: Further Evidence for the Shared Epitope Hypothesis. Arthritis Rbeum, 1991, 34r43-47. The Yakima Indians have a high frequency of expression of the Dwl6 variant of DR6, which shares the same third hypervariable region sequence as DR4Dw14 and DRl. Along with these alleles, DwI6 is associated with RA. GAO X, GAZE E, LNNEH A, SZWNY P: Rheumatoid Arthritis in Israeli Jews: Shared Sequences in the Third Hypervariable Region of DRBl AlIeles are Associated with Susceptibility. J Rbeumatol 1991, 18:801-803. Although the usual Caucasian susceptibility alleles such as Dw4 are uncommon in Israeli Jews, structurally similar alleles such as DRwlO and Dw15 are relatively common among those individuals with RA.
15. .
16. .
BOKI KA, PANA~I GS, VAUGHAN RW, DROSZOSAA, MOIJTSOPOIILOS HM, IANCHBURY JS: HLA Class II Sequences Polymor-
phism in Greeks: HLA-DRB Shared Epitope Hypothesis Accounts for the Disease in only a Minority of Patients. Arthritis Rbeum 1992, 35:74+760. The association between HLA and RA appears to be weaker in Greeks than other races. It remains to be shown whether this reflects different patterns of clinical disease or other genetic differences. SEGLIA.!J, LI EK, COHEN MG, WONG RWS, POTIER PK, So AK: between Rheumatoid Arthritis Susceptibility and the Presence of HLA-DR4 and DRj3 Alleiic Third Hypervariable Region Sequences in Southern Chinese Persons. Arthritis Rbeum 1992, 35~163-170. The Dw14 and Dw15 subtypes of DR4 predominate in Chinese patients with RA. There are suspicions that they tend to suffer fewer extra-articular complications. 17.
.
Linkage
Rheumatoid 18. ..
LWCHBURY JSS, JAEGER EEM, SANSOM DM, Hw MA, WORLISWORTHP, STEDEFORDJ, BELLJI, PANAYIGS: Strong Primary Selection for the Dw4 Subtype of DR4 Accounts for the HLA-DQw7 Association with Felty’s Syndrome. Hum Immunol 1991, 325664. This paper settles once and for all the controversy surrounding DR locus: it is of prime importance in determinating the severity of the Felty syndrome and the DQw7 association is secondaty to its linkage with Dw4.
WORDSWORTHBP, PII& KD, BUCKLEYJD, LWCHBURY JSS, OILIER . B, LUHROP M, BELLJl: HLA Heterozygosity Contributes to Susceptibility to Rheumatoid Arthritis. Am J Hum Genet 1992, 51:585-591. Combinations of alleles individually associated with RA (e g. Dw4/Dw14 or Dw4/DRl) are particulariy strong risk factors for severe RA. 19.
VAN ZEBEN D, HAZESJMW, ZWIDERMAN AH, C~rj A, SCHREUDER GMT, D’AMARo J, BREEDVELDFC: Association of HLA-DR4 with a more Progressive Disease Course in Patients with Rheumatoid Arthritis. Arthritis Rbeum 1991, 34:822-829. Careful clinical study correlating the severity of joint damage with possession of DR4.
20. .
21. .
SILMANAJ, HENNESSYE, OLLIERB: Incidence of Rheumatoid Arthritis in a Genetically Predisposed Population. Br J Rbeumatol 1992, 31:365-368. The expected increased risk of recurrence in the immediate relatives of probands with RA can be explained only in part by shared HIA haplo~ types, it also depends on other genetic factors. 22. .
ROUDIERJ, SETTE A, MONT A, ALBANIS, KARRksJC, CARSON Dk Tolerance to a Self Peptide from the Third Hypervariable Region of the E !3 Chain. Implications for Molecular Mimicry Models of Autoimmune Disease. Eur J Immunol 1991, 21:2063-2067. Could tolerance to selfHL4 peptides really be a means by which sus~ ceptible individuals might develop a hole in the immune repertoire allowing certain organisms to penetrate unimpeded? PA!.LWDX, WEST SG, LAFFERTY JA, CLEMENS JR, KAPPLERJW, MARRACKP, KOTZIN BL: Evidence for the Effects of a Superantigen in Rheumatoid Arthritis. Science 1991, 2533325-329. The apparent increase in VP14 usage by T cells in the joint raises the possibility of a superantigen effect. However, there are many potential technical difficulties with the ‘quantitative’ polymerase chain reaction (PCR) technique and subsequent studies in other laboratories have not generally confirmed these findings. 23. .
24. .
COOPER SM, DIER DL, ROESSNERKD, BIJDD KC, NICKL~~JA: Diversity of Rheumatoid Synovial Tissue T Cells by T Cell Receptor Analysis. Arthritis Rbeum 1991, 34537-543. Weak evidence that there may be a degree of oligoclonaiity in interleukin-2 responsive T cells isolated from the knee joint of a patient with RA HOWELL MD, D~VELEY JP, L~JNDEENKA, ESTY A, WINTERS ST, CARI,O DJ, BROSTOFF SW: Limited T-Cell Receptor Beta Chain Heterogeneity among IL-2 Receptor-positive Synovial T-cells Suggets a Role for Superantigen in Rheumatoid Arthritis. Proc Nat1 Acud Sci USA 1991, 88:10921-10925. One major problem with this type of study is that a major degree of bias may be introduced by culturing the T cells aspirated from the joint. Certain subsets may grow particularly efficiently in vitro and the final T-cell population might differ significantly from that seen in the joint for reasons other than sensitivity to interleukin-2. 25. .
26. .
PLUSCHKEG, RICKENG, TAUBE H, KRONONGERH, MELCHERS1, PETERHH, EICHMANNK, KRAWINKEL U: Biased T-cell Receptor V Alpha Region Repertoire in the SynovIaI Fluid of Rheumatoid Arthritis Patients. Eur J Immunol 1991, 21:274’+2754. Most studies so far have tended to concentrate on VP segments but this study demonstrates no alteration in the Vu repertoire. One question must be how relevant it is to look at cells in the synovial fluid rather than in the synovial membrane.
arthritis
Wordsworth
UEMATSI! Y, WEGE H, STRAUS A, O’rr M, BANNWAP~ W, IANCHBURYJ, PANAYIG, STEINMETZM: The T-cell Receptor Repertoire in the Synovial Fluid of a Patient with Rheumatoid Arthritis is Polyclonal. PYOCNutl Acad Sci USA 1991, 88:8534-8538. This study is notable for the successful use of the inverted PCR technique for amplifying T-cell receptor variable segmene and suggests an increase in VP2 usage. 27. .
C~RKILL MM, KIRK&%~BW, HA.SKARDDO. BAK~ATISC, GIBSON T, PANAYI GS: Gold Treatment of Rheumatoid Arthritis Decreases Synovial Expression of the Endothelial Leukocyte Adhesion Receptor ELAM-1. J Rbeumatol 1991, l&1453-1460. Although expression of Em-1 on synotial blood vessels was signifi candy reduced within two weeks of starting gold therapy this was not associated with a significant fall in the number of neutrophils within the joint. Iarger studies are needed. 28. .
MACGIUZCX)R AJ, SWAN AJ: Rheumatoid Factors as Predictors of Rheumatoid Arthritis. J Kheumatol 1991, 18:1280--1281. brief review for those in a hurry It highlights the presence of high levels of rheumatoid factor antedating the onset of RA in several prospective studies. 29.
MANNIK M: Rheumatoid Factors in the Pathogenesis of Rheumatoid Arthritis. J Rbeumatol 1992, 19 (suppl 32):4&49. Up-to-date review of the potential role of rheumatoid factors in RA
30. .
AHO K, HELIOVAARAM, MAATEIA J, TUOMI T, PALOSUO T: Rheumatoid Factors Antedating Clinical Rheumatoid Arthritis. J Rbeumatol 1991, 18:1282%1284. A long-term study that clearly demonstrates that while rheumatoid fact for is not specific for the development of the disease its presence can predate the onset of clinical symptoms by many years. 31. .
AXFORDJS: Oligosaccharides: an Optional Extra or of ReleVance to Disease Mechanisms in Rheumatology? J Rbeuma~ to1 1991, 18:11261127. A good review of the current knowledge of glycosylation defects in RA, although there are still clearly many unanswered questions about the cause and effect of these defects. 32. .
EMERY P, BRADLEYH, ARTHUR V, TUNN E, WAIUNG R: Genetic Factors Influencing the Outcome of Early Arthritis - the Role of Sulphoxidation Status. Br J Rbeumatol 1992, 31:449-451. A study of 55 subjects in an early arthritis clinic suggesting that sulphoxi&ion defects may help in the prediction of those destined to develop chronic RA. 33. .
REITER C, KAKAVANDB, RIEHER EP, SCHATTERNKIRCHNER G, KRUGER K: Treatment of Rheumatoid Arthritis with Monoclonal CD4 Antibody M-T151. Arthritis Kheum 1991, 34525-529. No definitive answers yet, but this form of therapy at least appears relatively safe. However, the development of anti-mouse antibodies in six of the trial subjects might prove a problem.
34. .
PANAYIGS, KIN(;SLEYGH, IANCHBLIRY JSS: Immunotherapy of Immune-mediated Diseases. Q J &fed 1992, 83:489495. this is a useful review of the preliminary studies investigating a potential therapeutic role for antibodies directed against cell surface receptors, including CD4, CD7, CD5 and the interleukin-2 receptor. 35
KERR LB, SPIERA H: The Co-existence of Active Classic Rheumatoid Arthritis and AIDS. J Rbeumatol 1991, 18:173!+1740. Anecdotal evidence that AIDS does not cure IL4 after all. 36. .
P Wordsworth, N&eld Department tal, Oxford OX3 9DU, UK.
of Medicine, John Radcliffe Hospi-
769
arthritis
Paul Wordsworth John
Rheumatoid
arthritis
which the abnormal agent(s) but progress been unrevealing. is slowly association
Radcliffe
is often considered immunological towards
In contrast,
becoming
Hospital,
clearer.
identifying
such
In particular,
extrinsic
Opinion
disease in
by an infectious
factors
has so far
of host susceptibility
the nature
of the HLA
class
II
into its pathogenesis
novel forms of therapy.
in immunology
Introduction arthritis (RQ is one of the commonest autoimmune diseases with a life-time incidence approaching 1 per cent in most populations worldwide, although there are some important exceptions to this. In common with many of these complex multifactorial disorders, such as type I diabetes mellitus and coeliac disease, there is emerging evidence to suggest that susceptibility to RA is determined by several genes [lo]. In this review I shall focus mainly on the genetic component of this disease, which can be divided into two parts-one part is associated with genes within the MHC and the other with genes outside the MHC. Despite the slow progress in identifying possible trigger factors [2*,3*], it is salutary to realize that the genetic component is probably relatively small since concordance rates in monozygotic twins are no more than 30 per cent and may be as low as 12 per cent [l-l. However, such twin studies can only give a very rough guide to the relative importance of genetic and non-genetic influences since they are beset both by problems of ascertainment bias and the potentially long delay (up to 40 years) which may occur before the second twin develops the disease . Furthermore, it is still not entirely clear whether the genetic factors are primarily important in determining the outcome of the disease rather than the initial susceptibility to synovitis, which may be self-limiting. As the locus within the MHC most closely associated with RA has been more precisely defined it has, at least, become somewhat easier to determine the full extent and nature of its contribution to the disease. Rheumatoid
Long-range
is triggered
with the disease has led to new insights
Current
UK
to be an autoimmune
response
the genetic component
and possible
susceptibility
Oxford,
1992, 4:76&769
identical HLA haplotypes, show a significant distortion from the expected random pattern of sharing [1*,4**]. Second, studies in outbred populations of most ethnic groups reveal associations with specific HIA markers, in particular with the class II antigen, DR4, in the majority of populations [ 5.1, These results indicate that genes linked to HLA must be involved, but does not prove that these genes themselves are necessarily of primary importance. However, since the associations with MHC class II markers are almost universally stronger than with class I, the area of interest must lie towards the centromeric end of the MHC, probably in the class II subregion. Nevertheless, the density of genes within the MHC (probably well over 100) still represents a considerable obstacle to the precise identification of the HLAlinked locus (or loci) involved in RA [6]. Considerable spice has been given to this search by the discovery of several loci within this region of the MHC that have potentially very important immunological functions. These include tumour necrosis factor (TNF)-CLand -p, heat shock protein 70, a number of complement proteins and, more recently, several loci located between the genes HLADP and -DQ, which encode proteins that play an important role in the cytosolit processing and transmembrane transport of antigens [7*]. Furthermore, it has been demonstrated by pulsefield gel electrophoresis that there is an apparent 100 000 nucleotide base pair inclusion between DR and DQ on all DR4 haplotypes relative to all other haplotypes; this could contain transcripts relevant to the development of RA [8] The association with HLADR4 could be equally well explained either by the direct involvement of DR4 or a tightly linked gene.
mapping of HLA-linked Fine mapping of HLA-linked
genes
susceptibility
genes Two parallel lines of investigation have clearly indicated a central role for genes within the MHC in the aetiology of RA. First, studies of siblings with RA, who have
Most DR haplotypes can be distinguished by their different DNA restriction fragment length polymorphisms,
Abbreviations AIDSacquired immune deficiency syndrome; ELAM--endothelial leukocyte adhesion molecule; HI_-human leukocyte-associated antigen; MHC-major histocompatibility complex; PCR-polymerase chain reaction; RA-rheumatoid arthritis; TN&tumour necrosis factor. 766
@
Current
Biology
Ltd ISSN
0925-7915
Rheumatoid
revealed by probes at the DR and DQ loci. However, this is not the case for the various subtypes of DR4 (of which there are at least 14 currently recognized). This indicates that there is a very high degree of conservation of the DNA on all DR4 haplotypes [9]. If there is differential susceptibility to RA associated with the various DR4 subtypes, it is most likely to be arising from the DRBl gene rather than from other genes in the flanking DNA, as polymorphism within this gene is responsible for generating the various DR4 subtypes [lo]. Several studies in caucasoids have now established that there is indeed a differential association of the disease with the DR4 subtypes [ 1l-131, thereby pinpointing DICE31as the primary locus responsible for RA within the HIA class II region. In addition to the positive associations with the DR4 subtypes, Dw4, Dw14 and Dw15, there are also associations with DRl in many populations, DRwlO in some and DRGDwl6 in the Yakima American Indians [ 141. Attempts to understand these apparently disparate associations have led to the development of the ‘shared epitope’ hypothesis of susceptibility. All these HL.4 molecules that are positively associated with susceptibility to RA share a high degree of amino acid sequence homology in the third allelic hypervariable region of the DRB-chain, which constitutes one side of the antigen-binding site. In particular, charged amino acid substitutions at positions 71 (DwlO) or 74 (Dw13), where the side chain is believed to point towards the binding site, abolish susceptibility to RA [12].
HLA-DR4: susceptibility
or severity
marker?
Even in populations in which there has not been a clear strong association of RA with a single HLA class II allele - such as Israeli Jews and Greeks-it is now clear that a combination of those alleles, bearing the shared susceptibility epitope is associated with a significant risk of RA [ 15*,16*]. However, it is possible that in these ethnic groups the disease may be somewhat milder than in populations where Dw4 predominates, such as in northem Europe (H Moutsopoulos, personal communication). This may also be the case in Chinese patients where the predominant DR4 subtypes associated with the disease are Dw14 and Dw15 [17*]. Further evidence of an influence of HLA on the severity of the disease has come from studies of the Felty syndrome and relatively severe forms of erosive rheumatoid arthritis [ 18**,19°,20*]. First, it is clear that the Felty syndrome has an almost complete association with Dw4 [ 18**]. Second, more severe forms of RA are significantly associated with genotypes that contain the Dw4/Dw14 and Dw4/DRl alleles [ 18**,19*]. This observation has also been made from the pooled data from a number of previous studies and has led to the suggestion that the susceptibility linked to HL4 might be recessive in nature [4**]. Finally, a long-term follow up of multiple case families has determined that the expected risk of recurrence in the immediate relatives of probands developing the disease is related in part to HLA-linked genes and in part to other genetic factors [ 21.1.
How can we interpret
arthritis
Wordsworth
the HLA associations
of
RA? The strong HLA associations of RA appear to place antigen presentation to CD4+ T cells at the heart of the pathological processes involved. It is not difficult to envisage a restricted range of potentially arthritogenic peptides capable of binding to a limited array of HLA molecules with certain shared physicochemical characteristics. How ever, it is equally possible that this interaction is im portant at an earlier stage of T-cell ontogeny-namely, during the positive and negative selection of the T-cell repertoire in the thymus. In contrast, the possibility that there may be autoimmune responses (perhaps by molecular mimicry with some foreign antigen) directed against those DRB molecules associated with inflammatory arthritis seems to have been ruled out, at least in certain animal models [22-l.
Several studies have now examined the possibility that there may be a restricted usage of antigen receptor by T cells within the rheumatoid joint. Considerable interest was provoked by reports of preferential usage of the VP14 segment by synovial lymphocytes, raising the possibility of a superantigen effect, perhaps in response to an intra-articular pathogen [23*]. These results have not gained wide acceptance as yet and there is no really strong evidence to support the idea that there is clonetypic predominance in the intraarticular T-cell response in RA [24*-27-l. Of course, it is possible that activated lymphocytes could trafic to the synovium subsequent to activation at sites away from the joint. While this question has not been directly addressed for ‘I’cells, one recent paper has raised the intriguing possibility that the traf ficking of neutrophils to the inflamed synovium might be influenced by down-regulation of endothelial leukocyte adhesion molecule (ELAM)-1 expression by the adminis tration of sodium aurothiomalate [2x*]
Non-HLA
factors in RA
No account of RA would be complete without mention ing the role of rheumatoid factors and this 11~1sbeen IC cently reviewed [29-,30-l, It is of ~~~rticular interest that the presence of rheumatoid factor often seeni~ kJ prc date the development of the disease by man!. )cars [3 1. ! however, it cannot be regarded as a very specific Indicz tor of subsequent disease. Likewise, a full explanation for the widespread glycosylation defect which affects the Fc portion of IgG (the &and for rheumatoid factors) as well as many other biologically important molecules remam~ tantalizing but elusive [32*]. In addition, it ha.+ also been reported that an impaired ability to oxidize sulphur-containing compounds, such as S-~drbo~methylil-L-cl;steint-, is associated with RA. This may be a useful predictor of those patients seen in an early synovitis clinic who are likely to go on to progressive disease [ 33* 1.
767
768
Autoimmunitv
Potential
novel therapies
For the immediate future, therapies aimed at blocking some component of the ternary complex (HLA molecule-antigen-T-cell receptor), which is believed to be involved in the pathogenesis of RA, remain entirely speculative. However, a number of trials have been initiated with murine or chimeric anti-CD4 antibodies that it is hoped might influence the disease process by an action on CD4+ T cells [34-,35*]. For a while there was anecdotal evidence that the depletion of T cells, consequent on the development of acquired immune deficiency syn drome (AIDS), was associated with the amelioration of RA. However, a recent report of a patient with AIDS and RA, whose active synovitis did not improve, perhaps casts some doubts on this hypothesis [36-l.
5. .
WORDSWORTHBP, BELLJI: The Immunogenetics
of Rheumatoid Arthritis. Springer Seminars in Immunopatbology 1992, 14159-78. A useful review of the association of various HIA allels with RA in a variety of different ethnic groups. 6.
SARGENT CA, D~JNHAM I, CAMPBELL RD: Identification of Multiple HTF-island Associated Genes in the Human Major Histocompatability Complex Class III region. !24BO J 1989, 8:2305-2312.
BP, SALMON M: The HLA Class II Component of Susceptibility to Rheumatoid Arthritis. Buifliere’s Clin Rheumatol 1992, 6~325-336. This review introduces the possibility thar HLADR alleles may be the most relevant in determining persistence of joint disease rather than the Initial susceptibility to synovitis. 7. .
WOKUSWORTH
8.
D~JNHAMI, SARGENTCA, DA~KINS RL, CAMPBELLRD: An Anal-
ysis of Variation in the Long-range Genomic Organization of the Human Major Histocompatibility Complex Class II Region by Pulsed-field Gel Electrophoresis. Genomicr 1989, 5~787-796.
Conclusions Considerable progress has been made in the past year in elucidating and confirming the nature of the HLA class II association with RA. It is now recognized that HIADR4 is a marker for more aggressive forms of the disease and that particular combinations of susceptibility alleles (e.g. ~w4/~wl4) are associated with more severe forms of the disease, such as the Felty syndrome. Unfortunately, this has not yet been translated to any successful form of therapy, which may not be surprising since the HIAlinked component of the disease probably accounts for no more than 10 per cent of the whole. Meanwhile the search continues for the elusive pathogens that many believe underlie the triggering of the disease. References
and recommended
Papers of particular
interest, published
within the annual period of re-
1. WORDSWOR~-~ BP, BEU JI: Polygenic Susceptibility in . Rheumatoid Arthritis. Ann Rheum Dis 1991, 50:343-346. A comprehensive review of the relative importance of genetic and nongenetic factors in RA.
BURMESTER GR: Hit and Run or Permanent Hit? Is There Evidence for a Microbiological Cause for Rheumatoid Arthritis? J Rbeumatol 1991, l&1443-1445. A challenging review of the possible role of microorganisms in the pathogenesis of RA, including a summary of the various organisms that have been invoked. 2. .
3. SIU~ANAJ: Is Rheumatoid Arthritis and Infectious Disease? . Br Med J 1991, 303:20&201. A somewhat sombre view, but this is a useful review of progress so far towards identifying any infectious triggers in R4 suggesting that new leads are required. ..
NICKL~~ JA, NOREEN HT, SE%ALLM, BACH FM: Southern AnaIysis of DNA Polymorphism among Dw Subtypes of DR4. Hum Immunol 1985, 13:95-103.
10.
GREGER~ENPK, SHEN M, SONG QL, MERRYMANP, DEGARS, SEKI
I, MACJ: Molecular Diversity of HLA-DR4 Haplotypes. Proc Nut1 Acud Sci USA 1986, 83~2642-2646. 11.
RIGBY AS, SILMAN AJ, VOEU~ L, GREC~RY JC, OLLIER WER, KHAN MA, NEPOM GT, THOMSON G: Investigating the HLA
Component In Rheumatoid Arthritis. An Additive (Dominant) Mode of Inheritance is Rejected, a Recessive Model is Preferred. Genetic Epidemiol 1991, 8:153_175. This is a reallygoodread with plenty of references and a comprehensive review of many of the largest population and family studies reported in the world literature. The authors claim that analysis of HIA haplotype sharing between a&ted sibling pairs is more in keeping with a recessive rather than a dominant mode of inheritance of susceptibility at this locus.
NE~OM GT, BYERSP, SEYFWEDC, HEALEYIA, WILSKIEKR, STAGE D, NEPOM BS: HLA Genes Associated with Rheumatoid
Arthritis. Identification of Susceptibility AlIeles Using Specific Oligonucleotide Probes. Arthritis Rbeum 1989, 32:15-21. 12.
WORDSWORTHBP, IANCHBURYJSS, SAKKASLI, WEISH KI, PANAYI
GS, BELLJI: HLA-DR4 Subtype Frequencies in Rheumatoid Arthritis Indicate that DRF3I is the Major Susceptibility Locus Within the HLA Class II Region. Proc Nat1 Acad Sci USA 1989, 86:1004~10053. 13.
GAO XJ, OLSEN NJ, PINCUS T, STASH-NY P: HLA-DR AlIeles with Naturally Occurring Amino Acid Substitutions and Risk for Development of Rheumatoid Arthritis. Arthritis Rbeum 1990, 33:93%946.
14. .
WILKENS RF, NEPOM GT, MARKS J, NETTLES JW, NEPOM BS:
reading
view, have been highlighted as: . of special interest .. of outstanding interest
4.
9.
Association of HLA-Dw16 with RA in Yakima Indians: Further Evidence for the Shared Epitope Hypothesis. Arthritis Rbeum, 1991, 34r43-47. The Yakima Indians have a high frequency of expression of the Dwl6 variant of DR6, which shares the same third hypervariable region sequence as DR4Dw14 and DRl. Along with these alleles, DwI6 is associated with RA. GAO X, GAZE E, LNNEH A, SZWNY P: Rheumatoid Arthritis in Israeli Jews: Shared Sequences in the Third Hypervariable Region of DRBl AlIeles are Associated with Susceptibility. J Rbeumatol 1991, 18:801-803. Although the usual Caucasian susceptibility alleles such as Dw4 are uncommon in Israeli Jews, structurally similar alleles such as DRwlO and Dw15 are relatively common among those individuals with RA.
15. .
16. .
BOKI KA, PANA~I GS, VAUGHAN RW, DROSZOSAA, MOIJTSOPOIILOS HM, IANCHBURY JS: HLA Class II Sequences Polymor-
phism in Greeks: HLA-DRB Shared Epitope Hypothesis Accounts for the Disease in only a Minority of Patients. Arthritis Rbeum 1992, 35:74+760. The association between HLA and RA appears to be weaker in Greeks than other races. It remains to be shown whether this reflects different patterns of clinical disease or other genetic differences. SEGLIA.!J, LI EK, COHEN MG, WONG RWS, POTIER PK, So AK: between Rheumatoid Arthritis Susceptibility and the Presence of HLA-DR4 and DRj3 Alleiic Third Hypervariable Region Sequences in Southern Chinese Persons. Arthritis Rbeum 1992, 35~163-170. The Dw14 and Dw15 subtypes of DR4 predominate in Chinese patients with RA. There are suspicions that they tend to suffer fewer extra-articular complications. 17.
.
Linkage
Rheumatoid 18. ..
LWCHBURY JSS, JAEGER EEM, SANSOM DM, Hw MA, WORLISWORTHP, STEDEFORDJ, BELLJI, PANAYIGS: Strong Primary Selection for the Dw4 Subtype of DR4 Accounts for the HLA-DQw7 Association with Felty’s Syndrome. Hum Immunol 1991, 325664. This paper settles once and for all the controversy surrounding DR locus: it is of prime importance in determinating the severity of the Felty syndrome and the DQw7 association is secondaty to its linkage with Dw4.
WORDSWORTHBP, PII& KD, BUCKLEYJD, LWCHBURY JSS, OILIER . B, LUHROP M, BELLJl: HLA Heterozygosity Contributes to Susceptibility to Rheumatoid Arthritis. Am J Hum Genet 1992, 51:585-591. Combinations of alleles individually associated with RA (e g. Dw4/Dw14 or Dw4/DRl) are particulariy strong risk factors for severe RA. 19.
VAN ZEBEN D, HAZESJMW, ZWIDERMAN AH, C~rj A, SCHREUDER GMT, D’AMARo J, BREEDVELDFC: Association of HLA-DR4 with a more Progressive Disease Course in Patients with Rheumatoid Arthritis. Arthritis Rbeum 1991, 34:822-829. Careful clinical study correlating the severity of joint damage with possession of DR4.
20. .
21. .
SILMANAJ, HENNESSYE, OLLIERB: Incidence of Rheumatoid Arthritis in a Genetically Predisposed Population. Br J Rbeumatol 1992, 31:365-368. The expected increased risk of recurrence in the immediate relatives of probands with RA can be explained only in part by shared HIA haplo~ types, it also depends on other genetic factors. 22. .
ROUDIERJ, SETTE A, MONT A, ALBANIS, KARRksJC, CARSON Dk Tolerance to a Self Peptide from the Third Hypervariable Region of the E !3 Chain. Implications for Molecular Mimicry Models of Autoimmune Disease. Eur J Immunol 1991, 21:2063-2067. Could tolerance to selfHL4 peptides really be a means by which sus~ ceptible individuals might develop a hole in the immune repertoire allowing certain organisms to penetrate unimpeded? PA!.LWDX, WEST SG, LAFFERTY JA, CLEMENS JR, KAPPLERJW, MARRACKP, KOTZIN BL: Evidence for the Effects of a Superantigen in Rheumatoid Arthritis. Science 1991, 2533325-329. The apparent increase in VP14 usage by T cells in the joint raises the possibility of a superantigen effect. However, there are many potential technical difficulties with the ‘quantitative’ polymerase chain reaction (PCR) technique and subsequent studies in other laboratories have not generally confirmed these findings. 23. .
24. .
COOPER SM, DIER DL, ROESSNERKD, BIJDD KC, NICKL~~JA: Diversity of Rheumatoid Synovial Tissue T Cells by T Cell Receptor Analysis. Arthritis Rbeum 1991, 34537-543. Weak evidence that there may be a degree of oligoclonaiity in interleukin-2 responsive T cells isolated from the knee joint of a patient with RA HOWELL MD, D~VELEY JP, L~JNDEENKA, ESTY A, WINTERS ST, CARI,O DJ, BROSTOFF SW: Limited T-Cell Receptor Beta Chain Heterogeneity among IL-2 Receptor-positive Synovial T-cells Suggets a Role for Superantigen in Rheumatoid Arthritis. Proc Nat1 Acud Sci USA 1991, 88:10921-10925. One major problem with this type of study is that a major degree of bias may be introduced by culturing the T cells aspirated from the joint. Certain subsets may grow particularly efficiently in vitro and the final T-cell population might differ significantly from that seen in the joint for reasons other than sensitivity to interleukin-2. 25. .
26. .
PLUSCHKEG, RICKENG, TAUBE H, KRONONGERH, MELCHERS1, PETERHH, EICHMANNK, KRAWINKEL U: Biased T-cell Receptor V Alpha Region Repertoire in the SynovIaI Fluid of Rheumatoid Arthritis Patients. Eur J Immunol 1991, 21:274’+2754. Most studies so far have tended to concentrate on VP segments but this study demonstrates no alteration in the Vu repertoire. One question must be how relevant it is to look at cells in the synovial fluid rather than in the synovial membrane.
arthritis
Wordsworth
UEMATSI! Y, WEGE H, STRAUS A, O’rr M, BANNWAP~ W, IANCHBURYJ, PANAYIG, STEINMETZM: The T-cell Receptor Repertoire in the Synovial Fluid of a Patient with Rheumatoid Arthritis is Polyclonal. PYOCNutl Acad Sci USA 1991, 88:8534-8538. This study is notable for the successful use of the inverted PCR technique for amplifying T-cell receptor variable segmene and suggests an increase in VP2 usage. 27. .
C~RKILL MM, KIRK&%~BW, HA.SKARDDO. BAK~ATISC, GIBSON T, PANAYI GS: Gold Treatment of Rheumatoid Arthritis Decreases Synovial Expression of the Endothelial Leukocyte Adhesion Receptor ELAM-1. J Rbeumatol 1991, l&1453-1460. Although expression of Em-1 on synotial blood vessels was signifi candy reduced within two weeks of starting gold therapy this was not associated with a significant fall in the number of neutrophils within the joint. Iarger studies are needed. 28. .
MACGIUZCX)R AJ, SWAN AJ: Rheumatoid Factors as Predictors of Rheumatoid Arthritis. J Kheumatol 1991, 18:1280--1281. brief review for those in a hurry It highlights the presence of high levels of rheumatoid factor antedating the onset of RA in several prospective studies. 29.
MANNIK M: Rheumatoid Factors in the Pathogenesis of Rheumatoid Arthritis. J Rbeumatol 1992, 19 (suppl 32):4&49. Up-to-date review of the potential role of rheumatoid factors in RA
30. .
AHO K, HELIOVAARAM, MAATEIA J, TUOMI T, PALOSUO T: Rheumatoid Factors Antedating Clinical Rheumatoid Arthritis. J Rbeumatol 1991, 18:1282%1284. A long-term study that clearly demonstrates that while rheumatoid fact for is not specific for the development of the disease its presence can predate the onset of clinical symptoms by many years. 31. .
AXFORDJS: Oligosaccharides: an Optional Extra or of ReleVance to Disease Mechanisms in Rheumatology? J Rbeuma~ to1 1991, 18:11261127. A good review of the current knowledge of glycosylation defects in RA, although there are still clearly many unanswered questions about the cause and effect of these defects. 32. .
EMERY P, BRADLEYH, ARTHUR V, TUNN E, WAIUNG R: Genetic Factors Influencing the Outcome of Early Arthritis - the Role of Sulphoxidation Status. Br J Rbeumatol 1992, 31:449-451. A study of 55 subjects in an early arthritis clinic suggesting that sulphoxi&ion defects may help in the prediction of those destined to develop chronic RA. 33. .
REITER C, KAKAVANDB, RIEHER EP, SCHATTERNKIRCHNER G, KRUGER K: Treatment of Rheumatoid Arthritis with Monoclonal CD4 Antibody M-T151. Arthritis Kheum 1991, 34525-529. No definitive answers yet, but this form of therapy at least appears relatively safe. However, the development of anti-mouse antibodies in six of the trial subjects might prove a problem.
34. .
PANAYIGS, KIN(;SLEYGH, IANCHBLIRY JSS: Immunotherapy of Immune-mediated Diseases. Q J &fed 1992, 83:489495. this is a useful review of the preliminary studies investigating a potential therapeutic role for antibodies directed against cell surface receptors, including CD4, CD7, CD5 and the interleukin-2 receptor. 35
KERR LB, SPIERA H: The Co-existence of Active Classic Rheumatoid Arthritis and AIDS. J Rbeumatol 1991, 18:173!+1740. Anecdotal evidence that AIDS does not cure IL4 after all. 36. .
P Wordsworth, N&eld Department tal, Oxford OX3 9DU, UK.
of Medicine, John Radcliffe Hospi-
769
