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HLA class II alleles and genetic predisposition to the antiphospholipid syndrome
Autoimmunity Reviews 2 (2003) 387–394
HLA class II alleles and genetic predisposition to the antiphospholipid syndrome Gian Domenico Sebastiania,*, Giovanni Minisolaa, Mauro Galeazzib,1 a
Unita` Operativa Complessa di Reumatologia, Azienda Ospedaliera San Camillo – Forlanini, Circonvallazione Gianicolense n. 87, 00152 Rome, Italy b Istituto di Reumatologia, Universita` di Siena, Siena, Italy Received 12 September 2002; accepted 20 May 2003
Abstract The antiphospholipid syndrome (APS) is an autoimmune disease characterized by the presence of antiphospholipid antibodies (aPL). Its etiology is linked to genetic predisposition, which is accounted for, at least in part, by genes of major histocompatibility complex (HLA system). The association of APS with human leukocyte antigen (HLA) alleles is a consequence of the association of aPL with HLA alleles. Some HLA alleles carry the risk to produce aPL, and this is independent of the clinical context. In fact, we find the same associations between HLA and aPL in primary APS and in APS secondary to systemic lupus erythematosus (SLE). The association of HLADR4, -DR7, -DRw53 and -DQB1*0302 with aCL that has been demonstrated in primary APS can also be found in SLE, a disease with a completely different pattern of HLA allele association (DR2, DR3, DRw52). In addition, the various aPL (anticardiolipin antibodies, lupus anticoagulant, anti-b2 GPI antibodies, antiphosphatidylseriney prothrombin antibodies) show similar HLA association, again independent of the clinical context (primary APS or SLE), and across various ethnic groups. 䊚 2003 Elsevier B.V. All rights reserved. Keywords: HLA; Antiphospholipid syndrome; Antiphospholipid antibodies; Immunogenetics
1. Introduction The antiphospholipid syndrome (APS) is an autoimmune disease characterized by the presence of antiphospholipid antibodies (aPL) in serum together with clinical manifestations such as
*Corresponding author. Tel.: q39-0658704218y4335; fax: q39-0658704250. E-mail address: [email protected] (G. Domenico Sebastiani). 1 Tel.: q39-0577233343; fax: q39-057740450.
thrombosis (both arterial and venous), fetal losses, hemolytic anemia and thrombocytopenia w1x. There is little doubt as to the pathogenic role of aPL in determining the clinical manifestations of APS, even if their mechanism of action has not been clarified. However, the etiology of APS is still unknown. Like in many other autoimmune diseases, this syndrome should arise in a predisposed subject after antigenic stimuli from various sources. Proofs of the genetic predisposition of APS lie on the observation of familiar clustering of cases, greater
1568-9972/03/$ - see front matter 䊚 2003 Elsevier B.V. All rights reserved. doi:10.1016/S1568-9972Ž03.00068-5
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prevalence of aPL in the serum of subjects sharing the same descent of patients, animal models (mice) and association with human leukocyte antigen (HLA) alleles. The present review will focus on this latter aspect. 1.1. Family studies Dagenais et al. described an English Canadian family in which anti-cardiolipin antibodies (aCL) were associated with a spectrum of clinical manifestations, from asymptomatic carriers to the typical thrombotic disease in association with systemic lupus erythematosus (SLE) and autoimmune thyroid disease w2x. They found the paternal haplotype A30; Cw3; B60; DR4; DRw53; DQw3 to be associated with aCL. However, the same haplotype was also present in a healthy subject without aCL and lupus anticoagulant (LA). The occurrence of LA in families carrying haplotypes that contained either DR4 or DR7 also has been reported by others w3–5x. May et al. have described a family, including identical twins and their mother, in which all members had SLE and presented with different manifestations of APS w6x. The mother and the twins shared the HLA haplotype that included DR4, DRw53 and DQw7, whereas C4A or C4B deficiencies could not be implicated in the autoimmune process. Another 21-year-old son was HLA identical to the twins; he had lived with his mother and the twins since birth and he did not have evidence of aPL or any other clinical and serologic abnormality. A sister sharing the APSassociated haplotype also was clinically and serologically normal. Again, these findings indicate that HLA contributions are not the sole determinant of autoantibody production or disease expression in APS. Other non-MHC-linked genes or environmental factors could be implicated. Familial occurrence of aCL has been documented by others w7x. 1.2. Population studies on primary antiphospholipid syndrome In a study of primary APS and HLA associations, as detected by molecular methods, HLA-
DQw7 (DQB1*0301 allele) was significantly associated with disease. All patients with DQw7 were HLA-DR4 or DR5 positive w8x. An association has also been claimed with DRw53 w9x. Asherson et al. reported on 13 English patients with primary APS, in which both class II genes and class III genes were examined by molecular methods w10x. They found that significant differences were limited to the HLA class II region of the MHC. In fact, DR4 and DRw53 were found with increased frequency in patients compared with controls, whereas DR3 was absent in all patients. ` et al. analysed HLA class II Camps Garcıa antigens in 19 patients from the South of Spain w11x. They showed that primary APS is associated with DR4, DQw7 and DRw53. Granados et al. reported an increase in DR7 in Mexican patients with primary APS w12x. More recently, Caliz et al. found that the haplotypes DQB1*0301y4-DQA1*0301y2-DRB1*04 and DQB1*0604y5y6y7y9-DQA1*0102DRB1*1302 were more frequent in 53 British Caucasoid patients with the primary APS than in controls w13x. The most striking association was found between DQB1*0604y5y6y7y9DQA1*0102-DRB1*1302 and anti-b2GPI antibodies (ab2GPI) in primary APS. The DQB1*0301y 4-DQA1*0301y2-DRB1*04 haplotype was also associated with antiphosphatidylserineyprothrombin autoantibodies in the same group of patients w14x. Another study reports the association of HLA-DR5 with primary APS in Mexican patients w15x. 1.3. Population studies on antiphospholipid antibodies in diseases other than primary APS Anticardiolipin antibodies were associated with DR7 in SLE patients from Northern Italy w16x, and with DR4 in SLE patients from England w17x. In a large multicenter European study on SLE, both HLA-DR4 and DR7 were increased in aCLpositive patients, and aCL were significantly associated with DRw53. The association between DRw53 and aCL was also apparent in 17 patients with SLE and APS. They found no association between aCL and HLA-DQ or C4 alleles w18x.
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Interestingly, another DRw53 (DRB4)-associated allele, DRB1*0901, was found to be associated with b2GPI-dependent aCL in a Japanese group of patients with SLE w19x, suggesting that aCL production in Japanese patients with SLE might be genetically controlled by the HLA-DRB1*0901 allele or alleles in strong linkage disequilibrium with it. Indeed, DRB1*0901 shows a higher frequency in Japanese compared with Caucasians. Although also this finding points toward the fact that aCL are associated with DRw53 and that the association of aCL with DRw53-associated alleles (DR4, DR7, DR9) depends on their regional prevalence, it should be noted that only one or two DRw53-associated alleles are increased in the various patient groups. On the contrary, no association between aCL and either HLA-DR or DQ alleles was found by Gulko et al. in 46 Caucasians and 45 African Americans with SLE w20x. Similarly, in a study of 44 SLE patients from Central and Southern Italy, we did not find any significant association between aCL and HLA-DR antigens, although DR3 showed a trend for negative association and DR6 for positive association. In addition, DR6-positive patients had higher levels of aCL in serum w21x. We recently performed a very large study on approximately 600 patients with SLE, all of European origin w22,23x, analysing the association of aCL and ab2GPI with HLA class II alleles. Our data showed that aCL are positively associated with HLA-DRB1*04, -DRB1*07, -DQA1*0201, DQA1*0301, -DQB1*0302, -DPB1*1501, DPB1*2301, -DRB3*0301 and that ab2GPI have a positive association with -DQB1*0302, DPB1*0301, -DPB1*1901. DQA1*0501 and DRB3*0202 showed a negative association with aCL. For the first time it was demonstrated that aCL and ab2GPI are associated with HLADRB1*0402 and -DRB1*0403, among the alleles of the DRB1*04 series. Indeed, DRB1*0402 carried the highest relative risk for the presence of both aCL (RRs8.1) and ab2GPI (RRs4.6), and it was noteworthy that 75% of patients carrying the DRB1*0402 allele were aCL-positive. We could not find any association with alleles at DRB4 locus (DRw53), and we found that aCL
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are associated with DR4 in SLE patients both from Spain and Italy, two Latin countries. Thus, it can be argued that both DR4 and DR7 are independently associated with aCL and that aCL in patients with SLE are associated with alleles at DRB1 locus but not with those at DRw53 locus. According to our results it seems that DRB1*0402 and DRB1*0403 are slightly more important than DR7 and that the association with DRw53 is only apparent because patients typing positive for DRw53 possess haplotypes that also contain either DR4 or DR7. Moreover, our data suggested that the HLA alleles could be important in determining the isotype of aCL and ab2GPI. Indeed, the DRB1*04yDQB1*0302 alleles were associated with IgG aCL and IgG ab2GPI, while the DRB1*07yDQA1*0201 alleles were associated with IgA aCL. DQA1*0301 was associated with IgM aCL, and DRB3*0301 was associated with IgA aCL and IgG aCL. In addition, we found that aCL and some clinical manifestations shared the same HLA association. This was the case of the association of IgA aCL and Raynaud’s phenomenon with DRB1*07 and DQA1*0301, of haemolytic anaemia and IgM aCL with DQA1*0301 and of thrombocytopenia and IgG aCL with DRB3*0301. Therefore, we can speculate that the association of HLA alleles with particular clinical manifestations of APS, we found in this study, might be a consequence of the association of these alleles with aCL andyor ab2GPI. Three studies suggested that aPL may be associated with a particular HLA-DQB1 sequence that encodes seven consecutive residues (71TRAELDT77), shared by HLA-DQ6, DQ7, DQ8 and DQ9 w8,24,25x. On the contrary, results of our study indicate that the association with the TRAELDT sequence, previously found in smaller series, could be secondary to that with DQB1*0302. Arnett et al. analysed the association of ab2GPI with HLA class II alleles in three ethnic groups, Mexican Americans (41 patients), white Americans (122 patients) and black Americans (99 patients) w25x. Authors examined rather an etherogeneous group of patients affected by primary APS, SLE and other connective tissue diseases.
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They found that HLA-DR4 haplotypes, especially those carrying HLA-DQ8 (DQB1*0302), are strongly associated with ab2GPI in whites and Mexican Americans, and less so in blacks, who normally have low frequencies of these alleles. In addition, they found that the HLA-DRB1*1302; DQB1*0604y0605 haplotype was associated with ab2GPI primarily in blacks, a result similar to that recently reported by Caliz et al. in a completely different ethnic group, British Caucasoid patients with primary APS w13x. In addition, Arnett et al. found a strong negative association between HLADR2 (DRB1*1501y*1503); DQ6 (DQB1*0602) and ab2GPI, thus confirming the results of previous studies that had shown a high prevalence of HLA-DR2 (DRB1*15) in lupus patients w26x but not in SLE patients with ab2GPI. We observed similar results in the European sample of lupus patients, where DRB1*15 was found to be increased in patients with SLE, but not in ab2GPI positive ones, suggesting a neutral effect, more than a protective role, of this allele on the production of these autoantibodies. Indeed, it is more likely that in Europeans the association of DR2 was with SLE itself or with other autoantibody specificities. In the study by Arnett, DQB1*0604y0605 was found to be positively associated with ab2GPI, while DQB1*0602 showed negative association. This apparent discrepancy may be explained by the evidence that, although similar, DQB1*0602 differs from DQB1*0604y5 most strikingly at position 57. In fact, the former antigen contains an aspartic acid residue at position 57, while *0604y05 contains a neutral amino acid (valine). Interestingly, HLA-DQB1*0302, which is associated with ab2GPI in European, white American and Mexican American populations with SLE, also contains a neutral aminoacid at position 57 (alanine). 2. Conclusions The APS may exist both as a primary condition as well as in the setting of another autoimmune disease (mainly SLE), and this implies possible differences in the association with HLA. Furthermore, aPL are a heterogeneous family of autoan-
tibodies. Some aPL can be found in autoimmune diseases, but others appear during the course of infectious diseases, neoplasias, or are drug related; they can also be present as an isolated phenomenon in healthy individuals. Their presence is not always associated with the clinical manifestations of APS, and even in experimental animal models not all aPL are of pathogenetic significance w27x. Some aPL bind preferentially to anionic phospholipids, whereas others react with zwitterionic phospholipids, and their binding can be either enhanced or depressed by b2GPI, depending on the source of aPL. Therefore, what we call ‘antiphospholipid antibodies’ may comprise a group of antibodies whose unique common feature is their reactivity against phospholipids, but with different specificity and different HLA associations. We favour the hypothesis that the association of APS with HLA alleles is a consequence of the association of aPL with HLA alleles. Some HLA alleles carry the risk to produce aPL, and this is independent of the clinical context. In fact, we find the same associations between HLA and aPL in primary APS and in APS secondary to SLE. The association of HLA-DR4, -DR7, -DRw53 and -DQB1*0302 with aCL that has been demonstrated in primary APS can also be found in SLE, a disease with a completely different pattern of HLA allele association (DR2, DR3, DRw52). In addition, the various aPL (aCL, LA, ab2GPI, antiphosphatidylserineyprothrombin antibodies) show similar HLA association, again independent of the clinical context (PAPS or SLE), and across various ethnic groups. Therefore, it is reasonable to think that, like in SLE, HLA alleles account only in part for the genetic susceptibility to develop APS. In fact, it appears that HLA alleles only determine the susceptibility to produce aPL, which are responsible for the clinical manifestations of APS. Other genes, even outside the MHC, give their contribution to the development of this autoimmune syndrome. For example, it has been shown that a polymorphism in domain 5 of b2GPI, valine instead of leucine at position 247, is correlated with ab2GPI production in patients with primary APS w28,29x. Furthermore, additional genetic risk factors for
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Table 1 Association between HLA alleles and antiphospholipid antibodies in various diseases Disease
aPL
HLA
Frequencya
Ethnic origin
Ref.
PAPS SLE SLE PAPSb SLE SLE SLE SLE SLE
aCL aCL aCL aCL aCL aCL aCL aCL aCL
DR4, DRw53, DQw3 DR7 DR4 DR4, DRw53 DR4, DR7, DRw53 DRB1*0901 DR, DQ DR DPB1*1401, 0301
– 61 87 56, 83 81 41 No association No association 45
English–Canadian Northern Italian English Australian Caucasian Japanese Caucasian and African American Central Italian Central Italian
w2x w16x w17x w32x w18x w19x w20x w21x w30x
SLE
aCL
aCL aCL
75y56,36 36,47, 45, 5, 8 No association No association
Caucasian
PSSc JCAd
DRB1*0402y3, DRB1*07, DQA1*0201, DQA1*0301, DQB1*0302, DPB1*1501, DPB1*2301 DR A, B, C, DR
PAPS
ab2GPI
DRB1*1302-DQA1*0102DQB1*0604y5y6y7y9
14
British Caucasoid
w13x
SLE
ab2GPI
w22x
ab2GPI ab2GPI ab2GPI aPTSyPTf
67y56, 50 35, 4 32 64–64 36–36 31–31 –35
European
PAPSqSLEe PAPSqSLEe PAPSqSLEe PAPS
DRB1*0402y3, DQB1*0302 DPB1*0301,DPB1*1901 DQB1*0302 DR4-DQB1*0302 DRB1*1302-DQB1*0604y5 DRB1*04-DQA1*0301y2DQB1*0301y4
White American Mexican American Black American British Caucasoid
w25x w25x w25x w14x
American Canadian
w22x w34x w35x
a
Frequency of HLA allele in aPL-positive patients (%). Patients with aCL and occlusion of coronary artery bypass grafts. c Primary Sjogren’s syndrome. d Juvenile chronic arthritis. e Forty-eight patients affected by PAPS, 196 patients affected by SLE, 18 patients affected by other connective tissue diseases (of whom 4 with APS). f Antiphosphatidylserineyprothrombin antibodies. b
thrombosis have been described in patients with APS, such as factor V Leiden, methylenetetrahydrofolate reductase, homocysteine, protein C or protein S deficiency, acquired activated protein C resistance. The role of these genetically determined factors in APS is not completely clarified, but it appears that they can act as additional (to aPL) thrombogenic risk factors. The various studies performed indicate that the HLA alleles most frequently associated with APS are HLA-DRB1*04 (DR4), DRB1*07 (DR7), DRB1*1302 (DR6), DRw53, DQA1*0102, DQA1*0201, DQA1*0301, DQB1*0302 (DQ8), DQB1*0604y5y6y7y9.
The association of aCL with HLA-DR4 and DR7 has been reported both in population studies on primary APS and in population studies on aCL in SLE, while other studies could not confirm these associations (Table 1) w30–32x. Furthermore, some studies suggested that aCL are associated with HLA-DRw53, an haplotype present in patients carrying either DR4 or DR7. Depending on the regional frequency of DR4 and DR7, this DRw53 association with aCL could be linked with either DR4 or DR7, with DR4 seeming more important in Anglo-Saxons and DR7 in Latins. On the contrary, in a study performed on a very large sample of European patients with SLE, we
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could not find any association with alleles at DRB4 locus (DRw53), and we found that aCL are associated with DR4 in SLE patients both from Spain and Italy, two Latin countries. Therefore, it can be argued that both DR4 and DR7 are independently associated with aCL. According to our results it seems that DRB1*0402 and DRB1*0403 are slightly more important than DR7 and that the association with DRw53 is only apparent because patients typing positive for DRw53 possess haplotypes that also contain either DR4 or DR7. Furthermore, it is hard to discriminate whether aCL and ab2GPI are more strongly associated with DR alleles or DQ alleles, because they are often in strong linkage disequilibrium. Alternatively, these alleles may be apparent only because of their linkage disequilibrium with an asyet unidentified primarily involved HLA locus, or they could act in co-operation with other genes, possibly even outside the MHC. For instance, some reports indicate that aCL are associated with C4A or C4B null alleles. Studies on primary APS indicate that it is genetically distinct from SLE. In fact, although DR3 is the class II allele of greatest importance in SLE w33x, this allele seems to be decreased in patients with the primary APS, where, by contrast, DR4, DR7 and DRw53 are the associated alleles. The picture is less clear if one looks at aPL. Of course, when these autoantibodies are found in patients with the primary APS, they show the same associations, but these HLA associations become less evident in SLE and disappear in other diseases, whether autoimmune or not. It seems that the association with DR4, DR7, DRw53 and DQB1*0302 in SLE is only evident when aCL are found in patients with secondary APS. Furthermore, the ethnic origin of the patients also influence the pattern of HLA associations. For example, some alleles may appear because their higher prevalence in a given ethnic group, such as DRB1*09 in Japanese population. In conclusion, immunogenetic studies suggest that APS is an entity distinct from SLE, even if it can appear in the course of this latter disease. The genetic predisposition to APS can be at least in part explained with an influence of certain HLA alleles. However, these alleles could only be appar-
ent because of their linkage disequilibrium with an as yet unidentified primarily involved HLAlocus, or they could act in co-operation with other genes, even residing outside the MHC. For this reason, the search for a more strongly associated polymorphism is actively pursued whenever new loci are identified in the HLA region. Acknowledgments We thank all the nurse staff of the Division of Rheumatology of San Camillo Hospital, Rome, for assistance in managing patients with the antiphospholipid syndrome. In particular Elsa Cusmano, Silvio Di Silvestro, Gloria Mambrini and Loris Panunzi. Take-home messages ● There is a genetic predisposition to develop the APS, which is in part accounted for by HLA alleles ● The association of APS with HLA alleles is a consequence of the association of antiphospholipid antibodies with HLA alleles ● HLA alleles carry the risk to produce aPL, and this is independent of the clinical context ● The HLA alleles most frequently associated with APS are HLA-DRB1*04 (DR4), DRB1*07, (DR7), DRB1*1302 (DR6), DRw53, DQA1*0102, DQA1*0201, DQA1*0301, DQB1*0302 (DQ8), DQB1*0604y5y6y7y9 ● Primary APS is genetically distinct from SLE ● The ethnic origin of the patients also influence the pattern of HLA association with APS
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with clinical and autoantibody subsets. Medicine 2002;81:169 –78. w34x Asherson RA, Fei H-M, Staub HL, Khamashta MA, Hughes GRV, Fox RI. Antiphospholipid antibodies and HLA associations in primary Sjogren’s syndrome. Ann Rheum Dis 1992;51:495 –8. w35x Malleson PN, Fung MY, Petty RE, Mackinnon MJ, Schroeder ML. Autoantibodies in chronic arthritis of childhood: relations with each other and with histocompatibility antigens. Ann Rheum Dis 1992;51:1301 –6.
The World of Autoimmunity; Literature Synopsis Anti-HuD antibodies induce neuronal apoptosis De Giorgio et al. (Gastroenterology 2003;125:70) tested whether anti-HuD-positive sera or commercial antiHuD antibodies could activate the apoptotic cascade in a neuroblastoma cell line and cultured myenteric neurons, and thus provide an explanation for a pathogenic role of these autoantibodies in paraneoplastic gut dysmotility. In neuroblasts SH-Sy5Y cells, the percentage of TUNEL-positive nuclei observed after exposure to anti-HuD-positive sera or anti-HuD antibodies was significantly greater than that of control sera or fetal calf serum. Similar results were found in myentric neurons exposed to anti-HuD antibodies. Apaf-1 and caspase-3 immunolabeling showed intense cytoplasmic staining in a significantly greater proportion of cells exposed to anti-HuD-positive sera or to commercial anti-HuD antibodies compared with controls. Hence, anti-HuD antibodies evoke neuronal apoptosis that may contribute to enteric nervous system impairment underlying paraneoplastic gut dysmotility.
Diabetes in congenital rubella syndrome Viskari et al. (Clin Exp Immunol. 2003;133:378) aimed to look for the mechanisms by which the rubella virus may cause diabetes and thyroid disease. They screened 37 subjects affected by or exposed to rubella during fetal life the incidence of clinical diabetes, thyroid disease, celiac disease and the following autoantibodies: islet cell antibodies, insulin autoantibodies, antibodies to the tyrosine phosphatase related IA2 molecule, and glutamic acid decarboxylase, thyroid peroxidase, tissue transglutaminase, and anti-gliadin autoantibodies. In this group, one patient had diabetes and four patients had hypothyroidism. Five patients tested positive for thyroid peroxidase autoantibodies, while the rest of autoantibodies could not be found in any of the patients. In addition, 8 patients carried the HLA-DR3-associated HLA-DQB1*02-DQA1*05 haplotype. In this cohort no increased frequency of markers for humoral beta-cell autoimmunity was detected in patients with congenital rubella syndrome. Thus, the mechanisms underlying diabetes in this context should be further investigated.
HLA class II alleles and genetic predisposition to the antiphospholipid syndrome Gian Domenico Sebastiania,*, Giovanni Minisolaa, Mauro Galeazzib,1 a
Unita` Operativa Complessa di Reumatologia, Azienda Ospedaliera San Camillo – Forlanini, Circonvallazione Gianicolense n. 87, 00152 Rome, Italy b Istituto di Reumatologia, Universita` di Siena, Siena, Italy Received 12 September 2002; accepted 20 May 2003
Abstract The antiphospholipid syndrome (APS) is an autoimmune disease characterized by the presence of antiphospholipid antibodies (aPL). Its etiology is linked to genetic predisposition, which is accounted for, at least in part, by genes of major histocompatibility complex (HLA system). The association of APS with human leukocyte antigen (HLA) alleles is a consequence of the association of aPL with HLA alleles. Some HLA alleles carry the risk to produce aPL, and this is independent of the clinical context. In fact, we find the same associations between HLA and aPL in primary APS and in APS secondary to systemic lupus erythematosus (SLE). The association of HLADR4, -DR7, -DRw53 and -DQB1*0302 with aCL that has been demonstrated in primary APS can also be found in SLE, a disease with a completely different pattern of HLA allele association (DR2, DR3, DRw52). In addition, the various aPL (anticardiolipin antibodies, lupus anticoagulant, anti-b2 GPI antibodies, antiphosphatidylseriney prothrombin antibodies) show similar HLA association, again independent of the clinical context (primary APS or SLE), and across various ethnic groups. 䊚 2003 Elsevier B.V. All rights reserved. Keywords: HLA; Antiphospholipid syndrome; Antiphospholipid antibodies; Immunogenetics
1. Introduction The antiphospholipid syndrome (APS) is an autoimmune disease characterized by the presence of antiphospholipid antibodies (aPL) in serum together with clinical manifestations such as
*Corresponding author. Tel.: q39-0658704218y4335; fax: q39-0658704250. E-mail address: [email protected] (G. Domenico Sebastiani). 1 Tel.: q39-0577233343; fax: q39-057740450.
thrombosis (both arterial and venous), fetal losses, hemolytic anemia and thrombocytopenia w1x. There is little doubt as to the pathogenic role of aPL in determining the clinical manifestations of APS, even if their mechanism of action has not been clarified. However, the etiology of APS is still unknown. Like in many other autoimmune diseases, this syndrome should arise in a predisposed subject after antigenic stimuli from various sources. Proofs of the genetic predisposition of APS lie on the observation of familiar clustering of cases, greater
1568-9972/03/$ - see front matter 䊚 2003 Elsevier B.V. All rights reserved. doi:10.1016/S1568-9972Ž03.00068-5
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prevalence of aPL in the serum of subjects sharing the same descent of patients, animal models (mice) and association with human leukocyte antigen (HLA) alleles. The present review will focus on this latter aspect. 1.1. Family studies Dagenais et al. described an English Canadian family in which anti-cardiolipin antibodies (aCL) were associated with a spectrum of clinical manifestations, from asymptomatic carriers to the typical thrombotic disease in association with systemic lupus erythematosus (SLE) and autoimmune thyroid disease w2x. They found the paternal haplotype A30; Cw3; B60; DR4; DRw53; DQw3 to be associated with aCL. However, the same haplotype was also present in a healthy subject without aCL and lupus anticoagulant (LA). The occurrence of LA in families carrying haplotypes that contained either DR4 or DR7 also has been reported by others w3–5x. May et al. have described a family, including identical twins and their mother, in which all members had SLE and presented with different manifestations of APS w6x. The mother and the twins shared the HLA haplotype that included DR4, DRw53 and DQw7, whereas C4A or C4B deficiencies could not be implicated in the autoimmune process. Another 21-year-old son was HLA identical to the twins; he had lived with his mother and the twins since birth and he did not have evidence of aPL or any other clinical and serologic abnormality. A sister sharing the APSassociated haplotype also was clinically and serologically normal. Again, these findings indicate that HLA contributions are not the sole determinant of autoantibody production or disease expression in APS. Other non-MHC-linked genes or environmental factors could be implicated. Familial occurrence of aCL has been documented by others w7x. 1.2. Population studies on primary antiphospholipid syndrome In a study of primary APS and HLA associations, as detected by molecular methods, HLA-
DQw7 (DQB1*0301 allele) was significantly associated with disease. All patients with DQw7 were HLA-DR4 or DR5 positive w8x. An association has also been claimed with DRw53 w9x. Asherson et al. reported on 13 English patients with primary APS, in which both class II genes and class III genes were examined by molecular methods w10x. They found that significant differences were limited to the HLA class II region of the MHC. In fact, DR4 and DRw53 were found with increased frequency in patients compared with controls, whereas DR3 was absent in all patients. ` et al. analysed HLA class II Camps Garcıa antigens in 19 patients from the South of Spain w11x. They showed that primary APS is associated with DR4, DQw7 and DRw53. Granados et al. reported an increase in DR7 in Mexican patients with primary APS w12x. More recently, Caliz et al. found that the haplotypes DQB1*0301y4-DQA1*0301y2-DRB1*04 and DQB1*0604y5y6y7y9-DQA1*0102DRB1*1302 were more frequent in 53 British Caucasoid patients with the primary APS than in controls w13x. The most striking association was found between DQB1*0604y5y6y7y9DQA1*0102-DRB1*1302 and anti-b2GPI antibodies (ab2GPI) in primary APS. The DQB1*0301y 4-DQA1*0301y2-DRB1*04 haplotype was also associated with antiphosphatidylserineyprothrombin autoantibodies in the same group of patients w14x. Another study reports the association of HLA-DR5 with primary APS in Mexican patients w15x. 1.3. Population studies on antiphospholipid antibodies in diseases other than primary APS Anticardiolipin antibodies were associated with DR7 in SLE patients from Northern Italy w16x, and with DR4 in SLE patients from England w17x. In a large multicenter European study on SLE, both HLA-DR4 and DR7 were increased in aCLpositive patients, and aCL were significantly associated with DRw53. The association between DRw53 and aCL was also apparent in 17 patients with SLE and APS. They found no association between aCL and HLA-DQ or C4 alleles w18x.
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Interestingly, another DRw53 (DRB4)-associated allele, DRB1*0901, was found to be associated with b2GPI-dependent aCL in a Japanese group of patients with SLE w19x, suggesting that aCL production in Japanese patients with SLE might be genetically controlled by the HLA-DRB1*0901 allele or alleles in strong linkage disequilibrium with it. Indeed, DRB1*0901 shows a higher frequency in Japanese compared with Caucasians. Although also this finding points toward the fact that aCL are associated with DRw53 and that the association of aCL with DRw53-associated alleles (DR4, DR7, DR9) depends on their regional prevalence, it should be noted that only one or two DRw53-associated alleles are increased in the various patient groups. On the contrary, no association between aCL and either HLA-DR or DQ alleles was found by Gulko et al. in 46 Caucasians and 45 African Americans with SLE w20x. Similarly, in a study of 44 SLE patients from Central and Southern Italy, we did not find any significant association between aCL and HLA-DR antigens, although DR3 showed a trend for negative association and DR6 for positive association. In addition, DR6-positive patients had higher levels of aCL in serum w21x. We recently performed a very large study on approximately 600 patients with SLE, all of European origin w22,23x, analysing the association of aCL and ab2GPI with HLA class II alleles. Our data showed that aCL are positively associated with HLA-DRB1*04, -DRB1*07, -DQA1*0201, DQA1*0301, -DQB1*0302, -DPB1*1501, DPB1*2301, -DRB3*0301 and that ab2GPI have a positive association with -DQB1*0302, DPB1*0301, -DPB1*1901. DQA1*0501 and DRB3*0202 showed a negative association with aCL. For the first time it was demonstrated that aCL and ab2GPI are associated with HLADRB1*0402 and -DRB1*0403, among the alleles of the DRB1*04 series. Indeed, DRB1*0402 carried the highest relative risk for the presence of both aCL (RRs8.1) and ab2GPI (RRs4.6), and it was noteworthy that 75% of patients carrying the DRB1*0402 allele were aCL-positive. We could not find any association with alleles at DRB4 locus (DRw53), and we found that aCL
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are associated with DR4 in SLE patients both from Spain and Italy, two Latin countries. Thus, it can be argued that both DR4 and DR7 are independently associated with aCL and that aCL in patients with SLE are associated with alleles at DRB1 locus but not with those at DRw53 locus. According to our results it seems that DRB1*0402 and DRB1*0403 are slightly more important than DR7 and that the association with DRw53 is only apparent because patients typing positive for DRw53 possess haplotypes that also contain either DR4 or DR7. Moreover, our data suggested that the HLA alleles could be important in determining the isotype of aCL and ab2GPI. Indeed, the DRB1*04yDQB1*0302 alleles were associated with IgG aCL and IgG ab2GPI, while the DRB1*07yDQA1*0201 alleles were associated with IgA aCL. DQA1*0301 was associated with IgM aCL, and DRB3*0301 was associated with IgA aCL and IgG aCL. In addition, we found that aCL and some clinical manifestations shared the same HLA association. This was the case of the association of IgA aCL and Raynaud’s phenomenon with DRB1*07 and DQA1*0301, of haemolytic anaemia and IgM aCL with DQA1*0301 and of thrombocytopenia and IgG aCL with DRB3*0301. Therefore, we can speculate that the association of HLA alleles with particular clinical manifestations of APS, we found in this study, might be a consequence of the association of these alleles with aCL andyor ab2GPI. Three studies suggested that aPL may be associated with a particular HLA-DQB1 sequence that encodes seven consecutive residues (71TRAELDT77), shared by HLA-DQ6, DQ7, DQ8 and DQ9 w8,24,25x. On the contrary, results of our study indicate that the association with the TRAELDT sequence, previously found in smaller series, could be secondary to that with DQB1*0302. Arnett et al. analysed the association of ab2GPI with HLA class II alleles in three ethnic groups, Mexican Americans (41 patients), white Americans (122 patients) and black Americans (99 patients) w25x. Authors examined rather an etherogeneous group of patients affected by primary APS, SLE and other connective tissue diseases.
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They found that HLA-DR4 haplotypes, especially those carrying HLA-DQ8 (DQB1*0302), are strongly associated with ab2GPI in whites and Mexican Americans, and less so in blacks, who normally have low frequencies of these alleles. In addition, they found that the HLA-DRB1*1302; DQB1*0604y0605 haplotype was associated with ab2GPI primarily in blacks, a result similar to that recently reported by Caliz et al. in a completely different ethnic group, British Caucasoid patients with primary APS w13x. In addition, Arnett et al. found a strong negative association between HLADR2 (DRB1*1501y*1503); DQ6 (DQB1*0602) and ab2GPI, thus confirming the results of previous studies that had shown a high prevalence of HLA-DR2 (DRB1*15) in lupus patients w26x but not in SLE patients with ab2GPI. We observed similar results in the European sample of lupus patients, where DRB1*15 was found to be increased in patients with SLE, but not in ab2GPI positive ones, suggesting a neutral effect, more than a protective role, of this allele on the production of these autoantibodies. Indeed, it is more likely that in Europeans the association of DR2 was with SLE itself or with other autoantibody specificities. In the study by Arnett, DQB1*0604y0605 was found to be positively associated with ab2GPI, while DQB1*0602 showed negative association. This apparent discrepancy may be explained by the evidence that, although similar, DQB1*0602 differs from DQB1*0604y5 most strikingly at position 57. In fact, the former antigen contains an aspartic acid residue at position 57, while *0604y05 contains a neutral amino acid (valine). Interestingly, HLA-DQB1*0302, which is associated with ab2GPI in European, white American and Mexican American populations with SLE, also contains a neutral aminoacid at position 57 (alanine). 2. Conclusions The APS may exist both as a primary condition as well as in the setting of another autoimmune disease (mainly SLE), and this implies possible differences in the association with HLA. Furthermore, aPL are a heterogeneous family of autoan-
tibodies. Some aPL can be found in autoimmune diseases, but others appear during the course of infectious diseases, neoplasias, or are drug related; they can also be present as an isolated phenomenon in healthy individuals. Their presence is not always associated with the clinical manifestations of APS, and even in experimental animal models not all aPL are of pathogenetic significance w27x. Some aPL bind preferentially to anionic phospholipids, whereas others react with zwitterionic phospholipids, and their binding can be either enhanced or depressed by b2GPI, depending on the source of aPL. Therefore, what we call ‘antiphospholipid antibodies’ may comprise a group of antibodies whose unique common feature is their reactivity against phospholipids, but with different specificity and different HLA associations. We favour the hypothesis that the association of APS with HLA alleles is a consequence of the association of aPL with HLA alleles. Some HLA alleles carry the risk to produce aPL, and this is independent of the clinical context. In fact, we find the same associations between HLA and aPL in primary APS and in APS secondary to SLE. The association of HLA-DR4, -DR7, -DRw53 and -DQB1*0302 with aCL that has been demonstrated in primary APS can also be found in SLE, a disease with a completely different pattern of HLA allele association (DR2, DR3, DRw52). In addition, the various aPL (aCL, LA, ab2GPI, antiphosphatidylserineyprothrombin antibodies) show similar HLA association, again independent of the clinical context (PAPS or SLE), and across various ethnic groups. Therefore, it is reasonable to think that, like in SLE, HLA alleles account only in part for the genetic susceptibility to develop APS. In fact, it appears that HLA alleles only determine the susceptibility to produce aPL, which are responsible for the clinical manifestations of APS. Other genes, even outside the MHC, give their contribution to the development of this autoimmune syndrome. For example, it has been shown that a polymorphism in domain 5 of b2GPI, valine instead of leucine at position 247, is correlated with ab2GPI production in patients with primary APS w28,29x. Furthermore, additional genetic risk factors for
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Table 1 Association between HLA alleles and antiphospholipid antibodies in various diseases Disease
aPL
HLA
Frequencya
Ethnic origin
Ref.
PAPS SLE SLE PAPSb SLE SLE SLE SLE SLE
aCL aCL aCL aCL aCL aCL aCL aCL aCL
DR4, DRw53, DQw3 DR7 DR4 DR4, DRw53 DR4, DR7, DRw53 DRB1*0901 DR, DQ DR DPB1*1401, 0301
– 61 87 56, 83 81 41 No association No association 45
English–Canadian Northern Italian English Australian Caucasian Japanese Caucasian and African American Central Italian Central Italian
w2x w16x w17x w32x w18x w19x w20x w21x w30x
SLE
aCL
aCL aCL
75y56,36 36,47, 45, 5, 8 No association No association
Caucasian
PSSc JCAd
DRB1*0402y3, DRB1*07, DQA1*0201, DQA1*0301, DQB1*0302, DPB1*1501, DPB1*2301 DR A, B, C, DR
PAPS
ab2GPI
DRB1*1302-DQA1*0102DQB1*0604y5y6y7y9
14
British Caucasoid
w13x
SLE
ab2GPI
w22x
ab2GPI ab2GPI ab2GPI aPTSyPTf
67y56, 50 35, 4 32 64–64 36–36 31–31 –35
European
PAPSqSLEe PAPSqSLEe PAPSqSLEe PAPS
DRB1*0402y3, DQB1*0302 DPB1*0301,DPB1*1901 DQB1*0302 DR4-DQB1*0302 DRB1*1302-DQB1*0604y5 DRB1*04-DQA1*0301y2DQB1*0301y4
White American Mexican American Black American British Caucasoid
w25x w25x w25x w14x
American Canadian
w22x w34x w35x
a
Frequency of HLA allele in aPL-positive patients (%). Patients with aCL and occlusion of coronary artery bypass grafts. c Primary Sjogren’s syndrome. d Juvenile chronic arthritis. e Forty-eight patients affected by PAPS, 196 patients affected by SLE, 18 patients affected by other connective tissue diseases (of whom 4 with APS). f Antiphosphatidylserineyprothrombin antibodies. b
thrombosis have been described in patients with APS, such as factor V Leiden, methylenetetrahydrofolate reductase, homocysteine, protein C or protein S deficiency, acquired activated protein C resistance. The role of these genetically determined factors in APS is not completely clarified, but it appears that they can act as additional (to aPL) thrombogenic risk factors. The various studies performed indicate that the HLA alleles most frequently associated with APS are HLA-DRB1*04 (DR4), DRB1*07 (DR7), DRB1*1302 (DR6), DRw53, DQA1*0102, DQA1*0201, DQA1*0301, DQB1*0302 (DQ8), DQB1*0604y5y6y7y9.
The association of aCL with HLA-DR4 and DR7 has been reported both in population studies on primary APS and in population studies on aCL in SLE, while other studies could not confirm these associations (Table 1) w30–32x. Furthermore, some studies suggested that aCL are associated with HLA-DRw53, an haplotype present in patients carrying either DR4 or DR7. Depending on the regional frequency of DR4 and DR7, this DRw53 association with aCL could be linked with either DR4 or DR7, with DR4 seeming more important in Anglo-Saxons and DR7 in Latins. On the contrary, in a study performed on a very large sample of European patients with SLE, we
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could not find any association with alleles at DRB4 locus (DRw53), and we found that aCL are associated with DR4 in SLE patients both from Spain and Italy, two Latin countries. Therefore, it can be argued that both DR4 and DR7 are independently associated with aCL. According to our results it seems that DRB1*0402 and DRB1*0403 are slightly more important than DR7 and that the association with DRw53 is only apparent because patients typing positive for DRw53 possess haplotypes that also contain either DR4 or DR7. Furthermore, it is hard to discriminate whether aCL and ab2GPI are more strongly associated with DR alleles or DQ alleles, because they are often in strong linkage disequilibrium. Alternatively, these alleles may be apparent only because of their linkage disequilibrium with an asyet unidentified primarily involved HLA locus, or they could act in co-operation with other genes, possibly even outside the MHC. For instance, some reports indicate that aCL are associated with C4A or C4B null alleles. Studies on primary APS indicate that it is genetically distinct from SLE. In fact, although DR3 is the class II allele of greatest importance in SLE w33x, this allele seems to be decreased in patients with the primary APS, where, by contrast, DR4, DR7 and DRw53 are the associated alleles. The picture is less clear if one looks at aPL. Of course, when these autoantibodies are found in patients with the primary APS, they show the same associations, but these HLA associations become less evident in SLE and disappear in other diseases, whether autoimmune or not. It seems that the association with DR4, DR7, DRw53 and DQB1*0302 in SLE is only evident when aCL are found in patients with secondary APS. Furthermore, the ethnic origin of the patients also influence the pattern of HLA associations. For example, some alleles may appear because their higher prevalence in a given ethnic group, such as DRB1*09 in Japanese population. In conclusion, immunogenetic studies suggest that APS is an entity distinct from SLE, even if it can appear in the course of this latter disease. The genetic predisposition to APS can be at least in part explained with an influence of certain HLA alleles. However, these alleles could only be appar-
ent because of their linkage disequilibrium with an as yet unidentified primarily involved HLAlocus, or they could act in co-operation with other genes, even residing outside the MHC. For this reason, the search for a more strongly associated polymorphism is actively pursued whenever new loci are identified in the HLA region. Acknowledgments We thank all the nurse staff of the Division of Rheumatology of San Camillo Hospital, Rome, for assistance in managing patients with the antiphospholipid syndrome. In particular Elsa Cusmano, Silvio Di Silvestro, Gloria Mambrini and Loris Panunzi. Take-home messages ● There is a genetic predisposition to develop the APS, which is in part accounted for by HLA alleles ● The association of APS with HLA alleles is a consequence of the association of antiphospholipid antibodies with HLA alleles ● HLA alleles carry the risk to produce aPL, and this is independent of the clinical context ● The HLA alleles most frequently associated with APS are HLA-DRB1*04 (DR4), DRB1*07, (DR7), DRB1*1302 (DR6), DRw53, DQA1*0102, DQA1*0201, DQA1*0301, DQB1*0302 (DQ8), DQB1*0604y5y6y7y9 ● Primary APS is genetically distinct from SLE ● The ethnic origin of the patients also influence the pattern of HLA association with APS
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The World of Autoimmunity; Literature Synopsis Anti-HuD antibodies induce neuronal apoptosis De Giorgio et al. (Gastroenterology 2003;125:70) tested whether anti-HuD-positive sera or commercial antiHuD antibodies could activate the apoptotic cascade in a neuroblastoma cell line and cultured myenteric neurons, and thus provide an explanation for a pathogenic role of these autoantibodies in paraneoplastic gut dysmotility. In neuroblasts SH-Sy5Y cells, the percentage of TUNEL-positive nuclei observed after exposure to anti-HuD-positive sera or anti-HuD antibodies was significantly greater than that of control sera or fetal calf serum. Similar results were found in myentric neurons exposed to anti-HuD antibodies. Apaf-1 and caspase-3 immunolabeling showed intense cytoplasmic staining in a significantly greater proportion of cells exposed to anti-HuD-positive sera or to commercial anti-HuD antibodies compared with controls. Hence, anti-HuD antibodies evoke neuronal apoptosis that may contribute to enteric nervous system impairment underlying paraneoplastic gut dysmotility.
Diabetes in congenital rubella syndrome Viskari et al. (Clin Exp Immunol. 2003;133:378) aimed to look for the mechanisms by which the rubella virus may cause diabetes and thyroid disease. They screened 37 subjects affected by or exposed to rubella during fetal life the incidence of clinical diabetes, thyroid disease, celiac disease and the following autoantibodies: islet cell antibodies, insulin autoantibodies, antibodies to the tyrosine phosphatase related IA2 molecule, and glutamic acid decarboxylase, thyroid peroxidase, tissue transglutaminase, and anti-gliadin autoantibodies. In this group, one patient had diabetes and four patients had hypothyroidism. Five patients tested positive for thyroid peroxidase autoantibodies, while the rest of autoantibodies could not be found in any of the patients. In addition, 8 patients carried the HLA-DR3-associated HLA-DQB1*02-DQA1*05 haplotype. In this cohort no increased frequency of markers for humoral beta-cell autoimmunity was detected in patients with congenital rubella syndrome. Thus, the mechanisms underlying diabetes in this context should be further investigated.