Elsevier

Human Immunology

Volume 67, Issue 6, June 2006, Pages 454-459
Human Immunology

HLA and RA Revisited: Citrullinated Food for the SE Hypothesis, the DR6 Effect, and NIMA

https://doi.org/10.1016/j.humimm.2006.03.016Get rights and content

Abstract

An obvious way to unravel the apparently complex association between human leukocyte antigen (HLA) and rheumatoid arthritis (RA) is to reduce the heterogeneity of this multifactorial disease. Recently we have discovered that shared epitope (SE)-positive HLA-DRB1 alleles are exclusively associated with a subgroup of RA patients that test positive for auto-antibodies against cyclic citrullinated peptides. Further studies suggested that SE-positive alleles are classical immune response genes for the development of these antibodies. On the basis of these and other data we formulated a two-hit model for the pathogenesis of RA which incorporates a novel “citrullinated” SE hypothesis. About 5 years ago Zanelli et al. reported that HLA-DR6 (*1301 and *1302) and some other DR alleles that share the DERAA-sequence on amino acids 70–74 of their third hypervariable region are associated with protection from (severe) RA. Recently we corroborated these data in a large prospective cohort study and demonstrated that protection was observed both in the presence and in the absence of a SE susceptibility allele on the other haplotype. Finally we review the state of the art of the association of noninherited maternal HLA antigens with both susceptibility to and protection from RA.

Introduction

Almost 25 years ago I was in charge of the research on “HLA and disease susceptibility” in the department founded and chaired by Jon van Rood and Jon himself was in charge of the research on “HLA and transplantation.” In my group much attention was being paid to HLA-DR3 and in Jon’s group the same was true for DR6. Therefore the shorthand for our research programs was “DR3” and “DR6.” For those who do not know this or have forgotten it: DR6 was different from the other DR antigens and at some stage it was thought that it might be a “null-allele” [1]. In those days it was common use in the department that a meeting was announced by the chairman or his secretary through the intercom. Once, when Jon announced his lab meeting, “DR6 is starting in 5 minutes”, I could not resist the temptation and called through the same intercom that reached everyone in the department “DR6 does not exist!” Jon was not amused.

Probably the main frustration of the “DR3” people was that we could never come up with a good explanation for our HLA and disease associations. The first reason that I have choosen HLA and rheumatoid arthritis (RA) as the subject for a review in this special Human Immunology issue is that we have recently made considerable progress in solving the shared epitope (SE) enigma.

The second reason is that I was of course wrong: DR6 not only exists but its influence also extends beyond the realm of transplantation into the “DR3”/autoimmune disease field. Ten years ago Zanelli et al. discovered that DR6 and some other DR alleles with an “alternative” SE in their third hypervariable region are associated with protection from RA. An extra reason to include it in this extra-special review is that this subject has at least until recently remained at least as controversal as the so-called “DR6 effect” in kidney transplantation.

The third part of this review is dedicated to Jon’s last pet: the noninherited maternal HLA antigens (NIMA’s) and their possible impact on both susceptibility to and protection from RA.

Section snippets

The shared epitope enigma

The HLA and RA enigma was introduced 30 years ago by Peter Stastny who discovered that HLA-DW4 as defined by mixed lymphocyte culture (MLC) typing was associated with RA [2]. His discovery was triggered by Astorga and Williams who observed 5 years earlier that MLC reactions between cells from RA patients were often negative or low [3]. With the development of serological and molecular typing of HLA class II antigens/molecules it gradually became clear that RA was associated with several

Toward a solution of the SE engima?

The main reason that RA is called an autoimmune disease is the association with the so-called rheumatoid factor (RF), an autoantibody reactive with the Fc part of IgG. The sensitivity and specificity of RF for RA are, however, low: 60–70 and 80–90%, respectively. Recently anticitrunillated protein/peptides autoantibodies (ACPA) that have a sensitivity similar to that of RF but a much higher specificity, namely up to 99% have been discovered [9]. Both RF and ACPA may be present (many) years

A citrullinated SE hypothesis

On the basis of these and some other data we proposed a two-hit model for the pathogenesis of RA in which the SE and ACPA play central roles [17].

In this model the first hit is the induction of ACPA. Citrullination has been described as a physiological process occurring during apoptosis at multiple sites in the body [18, 19, 20]. Five mammalian peptidyl arginine deiminases, PAD1–4 and PAD6, each with a defined tissue distribution, mediate citrullination of arginine in the presence of sufficient

The DR6 effect in RA

Ten years ago Zanelli et al. introduced a new shared epitope situated at the same position of the DRB1 molecule as the Q(R) R(K) RAA SE. DERAA-positive DRB1 molecules appeared to be associated with protection against RA. Mainly based on data obtained in the mouse CIA model Zanell et al. proposed the RA protection (RAP) hypothesis [32, 33]. In this hypothesis the DRB1 DERAA sequence functions not as a part of the p4 pocket of the DRB1 molecule but as a peptide that can bind to HLA class II

Lessons from our mother [36]

The concept that exposure of the immune system of the child to noninherited maternal antigens (NIMA) during pregnancy and breast feeding might have lifelong consequences for the allo-immune response of the child was first formulated in the 1950’s. The observation that rhesus-negative daughters of rhesus-positive mothers are less likely to form rhesus antibodies to daughters of rhesus negative mothers appeared to support this hypothesis. When these findings could not be confirmed, the NIMA

Acknowledgments

Dear Jon, You were not only one of the discoverers of The System that kept me and many others from the street and even from home; you were also the inspirator and organizer of arguably the best and in any case the most congenial department working on HLA immunogenetics in the world. Your creativity, intuition, energy, productivity, and enthusiasm are unique. You have been a real “bon patron” for me. Also thanks for your friendship, your jokes, stories, and anecdotes. Finally, for without asking

References (39)

  • P. Stastny

    Mixed lymphocyte cultures in rheumatoid arthritis

    J Clin Invest

    (1976)
  • G.P. Astorga et al.

    Altered reactivity in mixed lymphocyte culture of lymphocytes from patients with rheumatoid arthritis

    Arthritis Rheum

    (1969)
  • P.K. Gregersen et al.

    The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis

    Arthritis Rheum

    (1987)
  • R.F. Willkens et al.

    Association of HLA-Dw16 with rheumatoid arthritis in Yakima Indians. Further evidence for the “shared epitope” hypothesis

    Arthritis Rheum

    (1991)
  • B. Sanchez et al.

    HLA-DRw10 confers the highest susceptibility to rheumatoid arthritis in a Spanish population

    Tissue Antigens

    (1990)
  • W.E. Ollier et al.

    Is rheumatoid arthritis in Indians associated with HLA antigens sharing a DR beta 1 epitope?

    Ann Rheum Dis

    (1991)
  • M.M. Nielen et al.

    Specific autoantibodies precede the symptoms of rheumatoid arthritisa study of serial measurements in blood donors

    Arthritis Rheum

    (2004)
  • S. Rantapaa-Dahlqvist et al.

    Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis

    Arthritis Rheum

    (2003)
  • F.A. van Gaalen et al.

    Association between HLA class II genes and autoantibodies to cyclic citrullinated peptides (CCPs) influences the severity of rheumatoid arthritis

    Arthritis Rheum

    (2004)

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