Assessing Prognosis in Rheumatoid Arthritis Using Monoclonal Antibodies and Flow Cytometry

The HLA-DR4 association with rheumatoid arthritis (RA) was revealed in several pioneering observations by Stastny and others between 1974 and 1980 [1]. It is interesting that even in those early days there was an awareness that DR4 was not just associated with RA but was associated with severity of RA, as will be discussed later. As knowledge of the HLA system advanced and as further studies of RA were undertaken it became evident that the HLA association was by no means straightforward. For example, when it was found that DR4 was supertypic to a series of alleles - the subtypes of DR4 - it was noted that only a few of them were associated with RA; indeed one (DwlO or DRB1*0402) actually appeared to be protective. Later DR1 and DR14 were associated in some studies and DR10 was prominent in others. This confusing situation was considerably clarified when Gregersen et al. in 1987 [2] put forward the “shared epitope hypothesis”. These authors realised, from examination of the amino-acid sequence data that the alleles which were associated with RA all had a similar sequence in the beta chain, QKRAA or QRRAA at positions 70-74. This unifying hypothesis showed that the closest association between HLA and RA is with the shared sequence which lies on the edge of the MHC groove midway along one of its alpha helices. This is referred to as the “shared epitope”. The epitope concept leads into the purpose of this report which is to describe a series of monoclonal antibodies to DR4 and some of its subtypes as well as to the shared epitope. As will be discussed later, these antibodies may be useful in determining prognosis in early cases of RA.