The synovium of RA contains germinal centers with secondary follicles and abundant plasma cells that produce antibodies, some of which may be against self-antigens. Many of the serum autoantibodies detected in patients are specific for citrullinated peptides in which arginine residues are posttranslationally converted to citrulline. In RA, complexes of antibodies with citrullinated fibrinogen, type II collagen, α-enolase, and vimentin deposit in the joints. Evidence suggests that the anti-citrullinated protein antibodies (ACPA) in combination with a T cell response to the citrullinated proteins contribute to disease chronicity. Approximately 30% of RA patients do not have ACPA in the blood. About 80% of patients have serum IgM or IgA autoantibodies that bind to the Fc portions of their own IgG. These autoantibodies are called rheumatoid factor and may also deposit in joints as immune complexes, although they are not uniformly present in all patients with RA and can be found in patients without the disease.
It is estimated that 50% of the risk of developing RA is related to inherited genetic susceptibility. The HLA class II locus is associated with ACPA-positive RA. Evidence suggests that an epitope on a citrullinated protein, vinculin, mimics an epitope on many microbes and is the target of CD4+ T cells when presented by predisposing HLA-DQ alleles. A second gene linked to RA, PTPN22, encodes a protein tyrosine phosphatase that is postulated to inhibit T cell activation. Numerous other genetic associations have been reported.
Many candidate environmental factors whose antigens promote autoimmunity have been postulated. At least 70% of RA patients have ACPA in their blood, which may http://ebooksmedicine.net
Fig.21.35Comparisonofthemorphologicfeaturesofrheumatoidarthritisandosteoarthritis.
Susceptibility genes (HLA, other) Failure of tolerance, unregulated lymphocyte activation Environmental factors (e.g., infection, smoking) Enzymatic modification (e.g., citrullination) of self protein
T and B cell responses to self antigens (including antigens in joint tissues)
RAtypicallymanifestsassymmetricarthritisprincipallyaffectingthesmalljointsofthehandsandfeet.Grossly,thesynoviumbecomesedematous,thickened,andhyperplastic,transformingitssmoothcontourtoonecoveredbydelicateandbulbousvilli(
Fig.21.37A–B ).Thecharacteristichistologicfeaturesinclude(1)synovialcellhyperplasiaandproliferation;(2)denseinflammatoryinfiltratesofCD4+ helperTcells,Bcells,plasmacells,dendriticcells,andmacrophages(
Fig.21.37C );(3)increasedvascularityresultingfromangiogenesis;(4)neutrophilsandaggregatesoforganizingfibrinonthesynovialandjointsurfaces;(5)osteoclasticactivityinunderlyingbone,allowingthesynoviumtopenetrateintothebone,causingperiarticularerosionsandsubchondralcysts.Together,theaforementionedchangesproduceapannus:amassofedematoussynovium,inflammatorycells,granulationtissue,andfibroblaststhatgrowsoverthearticularcartilageandcausesitserosion.Inadvanceduntreatedcasesthepannuscanbridgethebonestoformafibrousankylosis,whichmaylaterossifyasabonyankylosis(
Fig.21.35