Lymphoid Aggregates That Resemble Tertiary Lymphoid Organs Define a Specific Pathological Subset in Metal-on-Metal Hip Replacements

Abstract

Aseptic lymphocyte-dominated vasculitis-associated lesion (ALVAL) has been used to describe the histological lesion associated with metal-on-metal (M-M) bearings. We tested the hypothesis that the lymphoid aggregates, associated with ALVAL lesions resemble tertiary lymphoid organs (TLOs). Histopathological changes were examined in the periprosthetic tissue of 62 M-M hip replacements requiring revision surgery, with particular emphasis on the characteristics and pattern of the lymphocytic infiltrate. Immunofluorescence and immunohistochemistry were used to study the classical features of TLOs in cases where large organized lymphoid follicles were present. Synchrotron X-ray fluorescence (XRF) measurements were undertaken to detect localisation of implant derived ions/particles within the samples. Based on type of lymphocytic infiltrates, three different categories were recognised; diffuse aggregates (51%), T cell aggregates (20%), and organised lymphoid aggregates (29%). Further investigation of tissues with organised lymphoid aggregates showed that these tissues recapitulate many of the features of TLOs with T cells and B cells organised into discrete areas, the presence of follicular dendritic cells, acquisition of high endothelial venule like phenotype by blood vessels, expression of lymphoid chemokines and the presence of plasma cells. Co-localisation of implant-derived metals with lymphoid aggregates was observed. These findings suggest that in addition to the well described general foreign body reaction mediated by macrophages and a T cell mediated type IV hypersensitivity response, an under-recognized immunological reaction to metal wear debris involving B cells and the formation of tertiary lymphoid organs occurs in a distinct subset of patients with M-M implants.

Do Patients With a Failed Metal-on-metal Hip Implant With a Pseudotumor Present Differences in Their Peripheral Blood Lymphocyte Subpopulations?

“…Interestingly, results of the present study also showed overall lower percentages of memory B cells in patients with a failed MoM hip implant with a pseudotumor than in patients with a well-functioning implant without a pseudotumor. These results may reflect the sequestration of memory B cells, possibly in secondary lymphoid organs or in periprosthetic tissues where lymphoid aggregates resembling tertiary lymphoid organs have been described in some patients with a MoM hip implant [29]. Interestingly, plasma cells have been found in periprosthetic tissues from failed MoM hip implants with a hypersensitivity reaction [38] and more specifically with a pseudotumor [32].…”

How Have New Bearing Surfaces Altered the Local Biological Reactions to Byproducts of Wear and Modularity?

“…A total of 34 publications fit our inclusion criteria (Appendix 1). [7,8,14], and others [19,26,27,29,34,40] have illustrated histologic features suggestive of an immune reaction in tissues around some failed metal-on-metal hip implants (see subsequently). These features are characteristic, but a failed metal-on-PE implant may demonstrate similar histologic findings [17,41].…”

“…First, by confining our review to studies that included quantitative or semiquantitative grading of the histologic findings, we excluded many publications that have used only qualitative descriptions of periarticular findings [5,12,29,35,42,44,46] or that have focused on particle quantitation [13,30,45], cytokine detection [9,21], or lymphocyte subsets [29]. Among the studies that have graded morphologic features of periprosthetic tissues, many have not included conventional metal-on-PE or ceramic-on-polyethylene cases as controls, and differences in grading criteria among studies preclude pooling the data into larger groups.…”

“…Some of the articles have identified subsets of lymphocytes associated with the inflammation (Table 1). Among those studies, Mital and coworkers [29] described morphological and lymphocyte phenotype proportions supporting the development of tertiary lymphoid organs with mixed B-and T-lymphocytes in 29% of 62 cases of failed metalon-metal hip implants. Although no nonmetal-on-metal controls were evaluated, the lymphoid aggregates and B-lymphocytes shown in this study further support an adaptive immune response in these patients.…”

“…The diffusely distributed chronic inflammation is often composed mainly of T-lymphocytes, whereas lymphoid aggregates are commonly combinations of B-and T-cells with occasional plasma cells [25,29,33]. These findings appear to be more common in either failed metal-on-metal hips [2,10,43] or in cases of failed nonmetal-on-metal hips in which metal particles can be identified [17].…”