Perivascular lymphocytic aggregates in hip prosthesis-associated adverse local tissue reactions demonstrate Th1 and Th2 activity and exhausted CD8 + cell responses

J Orthop Res. 2021 Dec;39(12):2581-2594. doi: 10.1002/jor.24998. Epub 2021 Feb 15.

Abstract

Hip implants are a successful solution for osteoarthritis; however, some individuals with metal-on-metal (MoM) and metal-on-polyethylene (MoP) prosthetics develop adverse local tissue reactions (ALTRs). While MoM and MoP ALTRs are presumed to be delayed hypersensitivity reactions to corrosion products, MoM- and MoP-associated ALTRs present with different histological characteristics. We compared MoM- and MoP-associated ALTRs histopathology with cobalt and chromium levels in serum and synovial fluid. We analyzed the gene expression levels of leukocyte aggregates and synovial fluid chemokines/cytokines to resolve potential pathophysiologic differences. In addition, we classified ALTRs from 79 patients according to their leukocyte infiltrates as macrophage-dominant, mixed, and lymphocyte-dominant. Immune-related transcript profiles from lymphocyte-dominant MoM- and MoP-associated ALTR patients with perivascular lymphocytic aggregates were similar. Cell signatures indicated predominantly macrophage, Th1 and Th2 lymphocytic infiltrate, with strong exhausted CD8+ signature, and low Th17 and B cell, relative to healthy lymph nodes. Lymphocyte-dominant ALTR-associated synovial fluid contained higher levels of induced protein 10 (IP-10), interleukin-1 receptor antagonist (IL-1RN), IL-8, IL-6, IL-16, macrophage inflammatory protein 1 (MIP-1α), IL-18, MCP-2, and lower cell-attracting chemokine levels, when compared with prosthetic revisions lacking ALTRs. In addition, the higher levels of IP-10, IL-8, IL-6, MIP-1α, and MCP-2 were observed within the synovial fluid of the lymphocyte-dominant ALTRs relative to the macrophage-dominant ALTRs. Not all cytokines/chemokines were detected in the perivascular aggregate transcripts, suggesting the existence of other sources in the affected synovia. Our results support the hypothesis of common hypersensitivity pathogenesis in lymphocyte-dominant MoM and MoP ALTRs. The exhausted lymphocyte signature indicates chronic processes and an impaired immune response, although the cause of the persistent T-cell activation remains unclear. The cytokine/chemokine signature of lymphocyte-dominant-associated ATLRs may be of utility for diagnosing this more aggressive pathogenesis.

Keywords: T-cell exhaustion; adverse local tissue reactions; cytokines; hip implants; perivascular aggregates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arthroplasty, Replacement, Hip* / adverse effects
  • CD8-Positive T-Lymphocytes
  • Chemokine CCL3
  • Chemokine CXCL10
  • Hip Prosthesis* / adverse effects
  • Humans
  • Interleukin-6
  • Interleukin-8
  • Lymphocytes
  • Metal-on-Metal Joint Prostheses* / adverse effects
  • Metals
  • Polyethylene
  • Prosthesis Design
  • Prosthesis Failure
  • Reoperation

Substances

  • Chemokine CCL3
  • Chemokine CXCL10
  • Interleukin-6
  • Interleukin-8
  • Metals
  • Polyethylene