G Fontecchio, L Ventura, R Azzarone, M A Fioroni, G Fornaciari, F Papola

Some paleopathological studies suggest that rheumatoid arthritis originated in the New World (among ancient Native American in Tennessee and neighbouring areas, 5000–500 BC); only after the discovery of America was the origin of the disease attributed to the Old World.1 In 1996, under the floors of the San Francisco church (Arezzo, Italy), a female mummy was discovered. This 50–55-year-old woman, re-named the ‘‘Braids Lady’’, died at the end of the 16th century. Several diagnostic examinations disclosed distinctive rheumatoid arthritis skeletal deformities due to rheumatoid arthritis in her body: large erosions of the metacarpophalangeal joints of the left hand; lateral deviation of all the fingers, with a typical ‘‘Z’’ deformation of the first one; and partial overlapping and fibular deviation of the toes, but no involvement of sacroiliac articulation, a prominent symptom of ankylosing spondylitis.2 It is well known that several autoimmune disorders are related to highly polymorphic and codominantly expressed antigens encoded by the human leucocyte antigen (HLA) complex. The association between rheumatoid arthritis and some of the alleles of the HLA-DRB1 locus, such as DRB1*0101, DRB1*0401, DRB1*0404, DRB1*0405, DRB1*1402, and to a lesser degree DRB1*1001, has been well established. A high percentage (.90%) of people affected by this disorder possess some alleles of the DRB1*01 or DRB1*04 gene families.3 Therefore, the purpose of this study was to define the HLA-DRB genotype of the ‘‘Braids Lady’’ and establish the presence or not of rheumatoid arthritis susceptibility genes. Molecular analysis was performed on DNA extracts of the mummy, and two different HLA typing techniques, polymerase chain reactionsequence- specific oligonucleotides (PCR-SSO) and PCRsequence- specific primers (PCR-SSP), were used to identify HLA-DRB alleles. The PCR-SSO analysis showed the presence of the DRB1*0101 and DRB1*1101 alleles (corresponding to DR1 and DR11 serotypes, respectively), with positivity for the DRB3 gene (phenotypically DR52). The assignment of the haplotype DRB1*0101 was confirmed by the results of the PCR-SSP test.
A pathogenetic hypothesis of rheumatoid arthritis that might well explain its worldwide diffusion is ‘‘molecular mimicry’’, resulting from a cross-reactive antibody response between certain microbial antigens (among which are Proteus mirabilis haemolysins and Epstein–Barr virus glycoprotein 110) and shared epitopes of some specific HLA-DR1, DR4 and DR14 susceptibility genes.4–6 Additionally, HLA-DRB1 alleles and the frequency of their shared epitopes may vary between different ethnic groups. For example, DRB1*0101, DRB1*0401, and *0404–05 share the epitope Q(K/R)RAA, which is associated with rheumatoid arthritis in Mediterranean patients, including Italians;7 DRB1*1402, 0802 and 0407, on the other hand, are absent or poorly represented in the Italian population, have a significantly higher gene frequency among Native Americans than other DRB1 alleles (Navajo and Pimans of the Gila River Indian community of Arizona, the Lakota Sioux, the Seri tribe of Northwest Mexico).8 9 Interestingly, among patients with rheumatoid arthritis from several Native American groups, neither HLA-DR1 nor DR4 was found to be associated with specific features of rheumatoid arthritis or the severity of the disease.10 Hence, it is more than probable that various aetiological agents could have acted on different susceptibility HLA alleles bearing shared epitopes and occurring with different frequencies within populations. Although the possession of rheumatoid arthritis risk-factor genes cannot be considered a diagnostic marker, the positive result for DRB1*0101 and the presence of rheumatoid arthritis features in the Italian mummy support the idea that this disease was present in the Old World since at least the mid-16th century.


Authors’ affiliations
G Fontecchio*, F Papola, Centro Regionale di Immunoematologia e Tipizzazione Tissutale, Azienda ASL n.4, P.le Collemaggio, L’Aquila, Italy
L Ventura, U. O. di Anatomia ed Istologia Patologica, Azienda ASL n. 4, L’Aquila, Italy
R Azzarone, M A Fioroni, G Fornaciari, Sezione di Storia della Medicina, Dipartimento di Oncologia, dei Trapianti e Nuove Tecnologie Mediche, Universita` di Pisa, Pisa, Italy

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