Rheumatoid arthritis (RA) is a chronic inflammatory arthritis affecting predominantly the hands and feet but it can involve almost any joint. The mean age of onset is later than in AS, usually in the forties, but it can occur at any age. It is three times as common in women as men and any model proposed to explain this disease must account for this characteristic feature.
RA occurs predominantly in individuals carrying HLA-DR1, some subtypes of HLA-DR4 (DW4, DW14 and DW15) and HLA-DR6 (DW16), but not in individuals carrying some other HLA-DR4 subtypes (DW10 and DW13). An examination of these susceptible HLA sequences demonstrated that the common denominator was the sequence QRRAA, present on the DRpi chain, encoding positions 70-74. The sequence closely resembles that found in HLA-DR4(DW4) individuals where there is a conservative substitution at position 71 from arginine to lysine.
In 1992, Ebringer and coworkers showed that there was molecular mimicry between the RA 'susceptibility sequence' EQRRAA and the sequence ESRRAL found in Proteus hemolysin. Furthermore, elevated titers of specific antibodies to Proteus mira-bilis in RA patients have been demonstrated by several groups. Wilson and coworkers went on to show that two separate sequences of Proteus mirabilis showed molecular mimicry with human self antigens: ESRRAL of Proteus hemolysin with EQRRAA of the HLA-DR1/DR4 susceptibility sequence and IRRET of Proteus urease (positions 337-341) with LRREI of a2 chain of type XI collagen (positions 421-425) (Figure 2). Type XI collagen is a component of hyaline cartilage frequently found in small joints and since erosions are a common characteristic of this disease, it could explain the anatomical locations of these lesions. Furthermore, specific antibodies were found, in RA patients, against the ESRRAL sequence of the susceptibility sequence DR1/DR4 but not against the EDERAA sequence found in HLA-DR4(DW10), a subtype not associated with this disease. Finally, RA patients had elevated titers of specific antibodies to purified Proteus hemolysin and urease when compared with AS patients and healthy controls. In a coded study involving 89 subjects, Wilson and coworkers found that Proteus could be isolated more frequently from the urine of RA patients attending an outpatient clinic compared with controls. A correlation was found between the anti-Pro-teus antibody titer and the number of colony-forming units grown from the urine specimens.
By 1997, specific elevations of anti-P roteus antibodies had been reported from ten different countries throughout the world and the perception was emerging that this microbe is a strong candidate for the etiological agent of this severe arthritic condition.
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