The Pathogenesis of Chronic Inflammation in Experimental Antigen-Induced Arthritis

Abstract

In an experimental arthritis induced by injection of bovine serum albumin or egg albumin into the joints of previously immunized animals, it has been demonstrated that the major portion of the radioactively labeled antigens injected was localized to avascular collagenous tissues in the joint, i.e., articular cartilage, menisci, and intra-articular ligaments. The antigens were partially eluted from the tissues with 5 M guanidine solution, but not with acid buffers or by 3 M magnesium chloride. The radioactive material eluted with guanidine was at least 80% precipitable by specific antisera. The radioactively labeled-inducing antigen was identified on the surface of articular collagenous tissues from arthritic joints by radioautography and immunofluorescence. Rabbit immunoglobulin and C3 were demonstrated in the same sites by immunofluorescence. The presence of specific antibody in collagenous tissues was demonstrated by the selective in vitro binding of 125I-labeled-inducing antigen to menisci from arthritic joints of immunized animals. The evidence obtained indicates that in this model of chronic arthritis, the inducing antigen persists for long periods of time in the form of immune complexes in the surface layers of the intra-articular collagenous tissue. The antigen retained in this form may be responsible for the chronicity of the synovitis by serving as a direct stimulus for the maintenance of prolonged antibody synthesis in the synovium and by providing a source of complement-fixing antigen-antibody complexes for the mediation of joint inflammation.

Pathogenesis of chronic inflammation in experimental ferritin‐induced arthritis.

“…The superficial distribution of large aggregates and the deep distribution of small suggested that penetration of the matrix occurred in relationship to size; this finding also supports the deposition of Ag as a formed complex. The specific staining of the aggregates for rabbit IgG, but lack of free staining for IgG in the matrix or joint space, suggests an initial local state of antigen excess without free antibody in either the tissue matrix or joint space (10). The aggregated form of Fn and its intense and highly specific staining for antibody add strong support to previous data for antigen locaiization in ACT as an immune complex (2.3,10,14,15).…”

“…The deposition of complexed Fn in almost normal appearing matrix surfaces continued up to 3 hours; a dramatic change occurring at 6 hours was associated with massive PMN cell interaction. This coincided with an intense Arthus reaction and in the continuing presence of immune complexes at a phase of Ag excess (10). At the Arthus peak, after 24 hours, severe damage has occurred with the surfaces stripped of their tangential layers, Fn, and cells.…”

“…At 6 hours, severe destructive changes in the surfaces occurred; collagen broke free and contributed to the inflammatory detritus. This change was accompanied by the continuing deposition of immune complexes in large amounts, in part relating to the destruction of the superficial matrix and paralleling the increasing amounts o f Fn complexes in the joint space (10). Many PMN cells at these surfaces actively phagocytosed complexes and probably surface debris, and their influx was followed by severe surface erosions.…”

“…If one accepts this interpretation, a mechanism of how ,18), already in the matrix, occurs which permits collagenolysis immediately around the immune complex-and hence its penetration. Such an occurrence may have important bearings on its binding and persistence in ACT (3,14,15). At 6 hours, severe destructive changes in the surfaces occurred; collagen broke free and contributed to the inflammatory detritus.…”

“…At sacrifice, ACT were obtained by careful joint dissection as previously outlined (10) and washed in PBS. For direct em study, the specimens were fixed in 3% glutaraldehyde and osmicated in 2% OsO,, dehydrated, and embedded in EPON in the usual manner ( 1 I ) .…”