Non‐inherited maternal HLA alleles are associated with rheumatoid arthritis (2022)

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January 2003

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S. Harney,

S. Harney

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J. Newton,

J. Newton

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A. Milicic,

A. Milicic

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M. A. Brown,

M. A. Brown

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B. P. Wordsworth

B. P. Wordsworth

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(Video) Rheumatoid arthritis - causes, symptoms, diagnosis, treatment, pathology

Rheumatology, Volume 42, Issue 1, January 2003, Pages 171–174, https://doi.org/10.1093/rheumatology/keg059

Published:

01 January 2003

Article history

Received:

19 March 2002

Accepted:

28 June 2002

Published:

01 January 2003

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    S. Harney, J. Newton, A. Milicic, M. A. Brown, B. P. Wordsworth, Non‐inherited maternal HLA alleles are associated with rheumatoid arthritis, Rheumatology, Volume 42, Issue 1, January 2003, Pages 171–174, https://doi.org/10.1093/rheumatology/keg059

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Abstract

Background. Rheumatoid arthritis (RA) is strongly associated with a series of HLA‐DRB1 alleles that encode a conserved sequence of amino acids (70Q/R K/R R A A74) in the DRβ1 chain, known as the shared epitope (SE). However 30% of patients are negative for DRB1*04 and 15% are SE‐negative. Exposure to these alleles as non‐inherited maternal antigens (NIMA) might explain this discrepancy. We undertook a family study to investigate the role of NIMA in RA.

Methods. One hundred families, including the RA proband and both parents, were recruited. HLA‐DRB1 genotyping was performed using an allele‐specific polymerase chain reaction by standard methods. The frequencies of NIMA and non‐inherited paternal antigens (NIPA) were compared using contingency tables and a two‐tailed P test. We then reviewed four previously published studies of NIMA in RA and conducted an analysis of the combined data

Results. We identified 36 families in which the proband was DRB1*04‐negative and 13 in which the proband lacked the SE. There was an excess of DRB1*04 and SE NIMA (P=0.05) compared with NIPA. Combined analysis with previous studies showed that 53/231 mothers (23%) versus 25/205 fathers (12%) had a non‐inherited DRB1*04 (P=0.003) and 30/99 mothers versus 18/101 fathers had a non‐inherited SE allele (P=0.03).

Conclusion. A role for HLA NIMA in RA is suggested by these results.

Rheumatoid arthritis, Shared epitope, Non‐inherited maternal alleles, HLA.

Rheumatoid arthritis (RA) is a polygenic disorder to which the HLA region contributes about 30% of the genetic component. It is associated with certain HLA‐DRB1 alleles encoding a conserved sequence of amino acids in the binding site of these antigen‐presenting molecules, often referred to as the shared epitope (SE) [1]. The strongest associations are with certain HLA‐DRB1*04 alleles (*0401, *0404, *0405 and *0408) but other SE‐positive DRB1 alleles (*0101, *0102 and *1001) are also associated with RA. However, because about 30% of patients are negative for DRB1*04 and 15% are SE negative, a unifying pathological mechanism has proven elusive. Recent observations suggest that biologically relevant exposure to HLA antigens may occur during fetal development and/or subsequently through the persistence (perhaps for life) of maternal cells in the offspring (‘microchimerism’). It has been suggested that persistent microchimerism may be involved in the pathogenesis of certain autoimmune diseases, such as scleroderma and thyroiditis [2, 3]. Autoimmune thyroid disease is particularly interesting because, like RA, it occurs more commonly in women and there is an increased incidence post‐partum. Thyroid disease is also more common in RA patients and their relatives than in the general population. We therefore feel that non‐inherited maternal HLA antigens (NIMA) may also play a role in RA. Previous reports have not uniformly confirmed this hypothesis, but few have had adequate statistical power to reject it [4–7]. We combined all previous reports, both positive and negative, to see if this effect was real. Although this was not ideal, we felt confident pooling these studies as they were remarkably similar from a number of viewpoints: all had probands with RA defined by the 1987 American College of Rheumatology criteria; all patients were European and thus belonged to a population in which the importance of the DRB1*04 is well established; and all the DRB1 typing was performed using the same method. Additionally, if you pool only the French and Dutch data (i.e. data for mainland Northern Europeans), the results are significant for the DRB1*04 data. Overall, in these studies the number of Southern Europeans included was very small, and this was important as DRB1*01 plays a bigger role than in British Caucasians

We therefore undertook a study of 100 nuclear families to investigate the possible involvement of NIMA in RA.

Methods

One hundred nuclear families (RA proband and both parents) were recruited from the Oxfordshire and Southwest UK regions. All the probands fulfilled the 1987 American College of Rheumatology criteria for RA [8]. The probands and both parents were genotyped for HLA‐DRB1 alleles, including DRB1*04 subtypes, by the polymerase chain reaction using sequence‐specific primers. Samples that were positive for DRB1*04 were then subtyped for an additional nine primers. The potential role of NIMA was investigated by comparing the frequencies of DRB1*04 NIMA and SE NIMA with those of the corresponding non‐inherited paternal antigens (NIPA). The results from four previous studies of the effects of NIMA in RA [4–7] were combined with those in our study for a combined analysis.

Statistical analysis

The frequencies of NIMA and NIPA were compared using contingency tables and a two‐tailed P test. We used Mietinnen's method for calculating confidence intervals. In the SE studies there were only 13 families but 26 pieces of data were used as both parents were included. Following our reviewer's comments, we did homogeneity tests (Table 1) and found that our data set was different from the Dutch and French data sets, so we re‐analysed their data separately.

Table 1.

Homogeneity tests

Study
Non‐inherited maternal and paternal allelesTransmitted vs non‐transmitted allelesPresent studyten Wolde [4]van der Horst [5]ECRAF familial [6]ECRAF sporadic [7]
NIMATrans912813850
NIMANot438315233158
NIPATrans4239523
NIPANot927365235159
Totals26797812681390
Expected values3.310.110.016.210.450.0
10.532.031.651.032.8158.0
1.54.74.67.44.823.0
10.632.231.851.433.0159.0
2679.078.0126.081.0390.0
χ29.60.30.40.60.5
4.11.10.00.00.0
4.01.50.60.30.0
0.20.80.60.00.1
17.93.81.51.00.7
Total24.9d.f.=12P=0.02
Study
Non‐inherited maternal and paternal allelesTransmitted vs non‐transmitted allelesPresent studyten Wolde [4]van der Horst [5]ECRAF familial [6]ECRAF sporadic [7]
NIMATrans912813850
NIMANot438315233158
NIPATrans4239523
NIPANot927365235159
Totals26797812681390
Expected values3.310.110.016.210.450.0
10.532.031.651.032.8158.0
1.54.74.67.44.823.0
10.632.231.851.433.0159.0
2679.078.0126.081.0390.0
χ29.60.30.40.60.5
4.11.10.00.00.0
4.01.50.60.30.0
0.20.80.60.00.1
17.93.81.51.00.7
Total24.9d.f.=12P=0.02

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Table 1.

Homogeneity tests

Study
Non‐inherited maternal and paternal allelesTransmitted vs non‐transmitted allelesPresent studyten Wolde [4]van der Horst [5]ECRAF familial [6]ECRAF sporadic [7]
NIMATrans912813850
NIMANot438315233158
NIPATrans4239523
NIPANot927365235159
Totals26797812681390
Expected values3.310.110.016.210.450.0
10.532.031.651.032.8158.0
1.54.74.67.44.823.0
10.632.231.851.433.0159.0
2679.078.0126.081.0390.0
χ29.60.30.40.60.5
4.11.10.00.00.0
4.01.50.60.30.0
0.20.80.60.00.1
17.93.81.51.00.7
Total24.9d.f.=12P=0.02
Study
Non‐inherited maternal and paternal allelesTransmitted vs non‐transmitted allelesPresent studyten Wolde [4]van der Horst [5]ECRAF familial [6]ECRAF sporadic [7]
NIMATrans912813850
NIMANot438315233158
NIPATrans4239523
NIPANot927365235159
Totals26797812681390
Expected values3.310.110.016.210.450.0
10.532.031.651.032.8158.0
1.54.74.67.44.823.0
10.632.231.851.433.0159.0
2679.078.0126.081.0390.0
χ29.60.30.40.60.5
4.11.10.00.00.0
4.01.50.60.30.0
0.20.80.60.00.1
17.93.81.51.00.7
Total24.9d.f.=12P=0.02

Open in new tab

Results

We identified 36 families in which the proband was HLA‐DRB1*04‐negative and only 13 in which the proband was SE‐negative. There was a non‐significant excess of DRB1*04 NIMA compared with NIPA (Table 2) and a significant excess of SE‐positive NIMA vs NIPA (P=0.05). The results of the combined analysis are shown in Table 2. There was a significant excess of DRB1*04 NIMA (23%) vs NIPA (12%), with an odds ratio of 2.1 (95% confidence interval 1.3–3.6) The incomplete data from some previous studies allowed us to undertake only a limited analysis of SE NIMA. Overall, 112 SE‐negative probands were identified; a significant excess of mothers (30%) compared with fathers (18%) carried an SE‐positive NIMA (P=0.04). As the French and Dutch data were remarkably similar and homogeneous when tests were done, we also combined these and found a similar significant result, with a P value of 0.01 (Table 3).

Table 2.

Comparison of NIMA and NIPA in DRB1*04‐ and SE‐negative patients with RA

(Video) Immunology of the rheumatoid joint
StudyNo. of DRB1*04‐ negative patientsDRB1*04‐ positive NIMADRB1*04‐ negative NIPAOdds ratio (95% CI)
Present study (UK)3612/366/362.5 (0.8–7.5)
ten Wolde et al., The Netherlands [4]5012/502/294.3 (0.9–20.6)
van der Horst et al., The Netherlands [5]398/393/393.1 (0.8–12.7)
Barrera et al., ECRAF (sporadic) [6]7213/659/611.44 (0.5–3.7)
Barrera et al., ECRAF (multicase) [7]518/415/401.94 (0.6–6.5)
Above five studies combined24853/23125/2052.1 (1.3–3.6)*
No. of SE patientsSE+ NIMASE+ NIPAOdds ratio (95% CI)
Present study (UK)139/134/135.1 (1.0–25.6)
van der Horst et al., The Netherlands [5]254/252/252.2 (0.4–13.2)
Barrera et al., ECRAF (sporadic) [6]4310/386/371.9 (0.6–5.7)
Barrera et al., ECRAF (multicase) [7]317/236/261.5 (0.4–5.2)
Above four studies combined11230/9918/1012.0 (1.04–3.9)**
StudyNo. of DRB1*04‐ negative patientsDRB1*04‐ positive NIMADRB1*04‐ negative NIPAOdds ratio (95% CI)
Present study (UK)3612/366/362.5 (0.8–7.5)
ten Wolde et al., The Netherlands [4]5012/502/294.3 (0.9–20.6)
van der Horst et al., The Netherlands [5]398/393/393.1 (0.8–12.7)
Barrera et al., ECRAF (sporadic) [6]7213/659/611.44 (0.5–3.7)
Barrera et al., ECRAF (multicase) [7]518/415/401.94 (0.6–6.5)
Above five studies combined24853/23125/2052.1 (1.3–3.6)*
No. of SE patientsSE+ NIMASE+ NIPAOdds ratio (95% CI)
Present study (UK)139/134/135.1 (1.0–25.6)
van der Horst et al., The Netherlands [5]254/252/252.2 (0.4–13.2)
Barrera et al., ECRAF (sporadic) [6]4310/386/371.9 (0.6–5.7)
Barrera et al., ECRAF (multicase) [7]317/236/261.5 (0.4–5.2)
Above four studies combined11230/9918/1012.0 (1.04–3.9)**

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Table 2.

Comparison of NIMA and NIPA in DRB1*04‐ and SE‐negative patients with RA

StudyNo. of DRB1*04‐ negative patientsDRB1*04‐ positive NIMADRB1*04‐ negative NIPAOdds ratio (95% CI)
Present study (UK)3612/366/362.5 (0.8–7.5)
ten Wolde et al., The Netherlands [4]5012/502/294.3 (0.9–20.6)
van der Horst et al., The Netherlands [5]398/393/393.1 (0.8–12.7)
Barrera et al., ECRAF (sporadic) [6]7213/659/611.44 (0.5–3.7)
Barrera et al., ECRAF (multicase) [7]518/415/401.94 (0.6–6.5)
Above five studies combined24853/23125/2052.1 (1.3–3.6)*
No. of SE patientsSE+ NIMASE+ NIPAOdds ratio (95% CI)
Present study (UK)139/134/135.1 (1.0–25.6)
van der Horst et al., The Netherlands [5]254/252/252.2 (0.4–13.2)
Barrera et al., ECRAF (sporadic) [6]4310/386/371.9 (0.6–5.7)
Barrera et al., ECRAF (multicase) [7]317/236/261.5 (0.4–5.2)
Above four studies combined11230/9918/1012.0 (1.04–3.9)**
StudyNo. of DRB1*04‐ negative patientsDRB1*04‐ positive NIMADRB1*04‐ negative NIPAOdds ratio (95% CI)
Present study (UK)3612/366/362.5 (0.8–7.5)
ten Wolde et al., The Netherlands [4]5012/502/294.3 (0.9–20.6)
van der Horst et al., The Netherlands [5]398/393/393.1 (0.8–12.7)
Barrera et al., ECRAF (sporadic) [6]7213/659/611.44 (0.5–3.7)
Barrera et al., ECRAF (multicase) [7]518/415/401.94 (0.6–6.5)
Above five studies combined24853/23125/2052.1 (1.3–3.6)*
No. of SE patientsSE+ NIMASE+ NIPAOdds ratio (95% CI)
Present study (UK)139/134/135.1 (1.0–25.6)
van der Horst et al., The Netherlands [5]254/252/252.2 (0.4–13.2)
Barrera et al., ECRAF (sporadic) [6]4310/386/371.9 (0.6–5.7)
Barrera et al., ECRAF (multicase) [7]317/236/261.5 (0.4–5.2)
Above four studies combined11230/9918/1012.0 (1.04–3.9)**

Open in new tab

Table 3.

Data from Dutch and French data sets

Studies (all referred to in [3])No. of DRB1*04‐ negative patientsDRB1*04‐ positive NIMADRB1*04‐ negative NIPAOdds ratio (95% CI)
ten Wolde et al., The Netherlands [4]5012/502/294.3 (0.9–20.6)
van der Horst et al., The Netherlands [5]398/393/393.1 (0.8–12.7)
Barrera et al., ECRAF (sporadic) [6]7213/659/611.44 (0.5–3.7)
Barrera et al., ECRAF (multicase) [7]518/415/401.94 (0.6–6.5)
Above four studies combined21241/19519/1692.1 (1.2–3.8) (P=0.01)
Studies (all referred to in [3])No. of DRB1*04‐ negative patientsDRB1*04‐ positive NIMADRB1*04‐ negative NIPAOdds ratio (95% CI)
ten Wolde et al., The Netherlands [4]5012/502/294.3 (0.9–20.6)
van der Horst et al., The Netherlands [5]398/393/393.1 (0.8–12.7)
Barrera et al., ECRAF (sporadic) [6]7213/659/611.44 (0.5–3.7)
Barrera et al., ECRAF (multicase) [7]518/415/401.94 (0.6–6.5)
Above four studies combined21241/19519/1692.1 (1.2–3.8) (P=0.01)

Open in new tab

Table 3.

Data from Dutch and French data sets

Studies (all referred to in [3])No. of DRB1*04‐ negative patientsDRB1*04‐ positive NIMADRB1*04‐ negative NIPAOdds ratio (95% CI)
ten Wolde et al., The Netherlands [4]5012/502/294.3 (0.9–20.6)
van der Horst et al., The Netherlands [5]398/393/393.1 (0.8–12.7)
Barrera et al., ECRAF (sporadic) [6]7213/659/611.44 (0.5–3.7)
Barrera et al., ECRAF (multicase) [7]518/415/401.94 (0.6–6.5)
Above four studies combined21241/19519/1692.1 (1.2–3.8) (P=0.01)
Studies (all referred to in [3])No. of DRB1*04‐ negative patientsDRB1*04‐ positive NIMADRB1*04‐ negative NIPAOdds ratio (95% CI)
ten Wolde et al., The Netherlands [4]5012/502/294.3 (0.9–20.6)
van der Horst et al., The Netherlands [5]398/393/393.1 (0.8–12.7)
Barrera et al., ECRAF (sporadic) [6]7213/659/611.44 (0.5–3.7)
Barrera et al., ECRAF (multicase) [7]518/415/401.94 (0.6–6.5)
Above four studies combined21241/19519/1692.1 (1.2–3.8) (P=0.01)

Open in new tab

Discussion

HLA molecules are crucial in the definition of self and are key determinants of transplant success. Their role in susceptibility to RA is well established but the disease processes involved have not yet been clarified. Our results, combined with previous studies, strongly suggest that HLA NIMA may also be involved in RA.

It has already been shown that NIMA can influence immunologically mediated processes. Thus, Burlingham et al. [9] showed that graft survival for siblings mismatched with the donor for the NIMA haplotype was similar to that of graft survival in HLA‐identical donors. It has been suggested that exposure to the NIMA haplotype in utero by transplacental transfusion may lead to tolerance. Maternal cells may persist in the fetus (and vice versa) in a process known as microchimerism, but whether this is necessary for tolerance to develop is unclear. Srivatsa et al. [10] recently demonstrated striking microchimerism in autoimmune thyroid disease, suggesting that it may play a significant role in autoimmunity. Microchimerism in thyroid disease is particularly interesting because of the high post‐partum incidence of subclinical thyroiditis. Thyroid disease and RA have several parallels: both are more common in women and tend to flare or present post‐partum. Nelson et al. [2] have highlighted the role of microchimerism in scleroderma. In contrast, Nelson [3] recently questioned whether microchimerism was just a remnant of healthy pregnancy. On the other hand, another article has reported a patient with a terminal thymic tumour that regressed after she received a stem‐cell infusion of her daughter's cells, which were mismatched for NIMA. However, the mechanisms by which NIMA might influence susceptibility to RA are as unclear as the role HLA molecules play in the process. The mechanisms by which B cell unresponsiveness to NIMA is induced are not yet established [11]. Microchimerism is found frequently in the blood of healthy parous women, and healthy offspring often possess maternal cells. Although we have been able to demonstrate a significant excess of DRB1*04 and SE NIMA in RA families, this effect is relatively weak. We have shown that, with increased study numbers, this effect exists. However, to date there has been no large study in RA to prove this hypothesis definitively. As highlighted recently by Nelson, the role of NIMA in human health and disease is worth further investigation [2] and appears to play a significant role in the pathogenesis of RA.

This work was supported by the Arthritis Research Campaign and the Grenville Bequest.

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