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Purpose: The gouty tophus is the hallmark of chronic gout. The aim of this study was to characterize the cellular architecture of the tophus, and to determine the presence of cytokines implicated in initiation and resolution of gouty inflammation.
Method: Sixteen fixed, paraffin-embedded, uninfected tophus samples were surgically obtained from twelve patients with microscopically proven gout. The samples were analyzed by quantitative immunohistochemistry. The number of cells present in the corona and fibrovascular zones of the tophus was analyzed by GENMOD mixed model analysis to account for repeated counts within the same individual.
Results: All results are summarized in the Table. Numerous CD68+ macrophages were present within the corona zone. The majority of these cells were mononucleated, but multinucleated CD68+ cells were also identified. Mast cells were present in all tophus samples, throughout the corona and fibrovascular zones in similar densities. In contrast, neutrophils were rarely observed. Plasma cells were present in very high numbers within the corona zone. The overall number of CD20+ B cells was much lower. However, in 5 of the 12 (42%) patients, at least one B cell aggregate was present in the fibrovascular zone. Large numbers of cells expressing IL-1β were observed, particularly within the corona zone, in both mononucleated and multinucleated cells. TGF-β1-expressing mononucleated cells were also identified. The number of cells expressing IL-1β correlated with the number expressing TGF-β1 (r=0.59, p=0.03). The number of CD68+ cells correlated with the number of cells expressing IL-1β (r=0.64, p=0.02) and TGF-β1 (r=0.63, p=0.009).
Conclusion: The tophus represents a complex and organized chronic inflammatory tissue response to MSU crystals. Both innate and adaptive immune cells are present within the gouty tophus, contrasting with the well recognized, dominant role of innate immunity in the acute gout attack. The co-expression of IL-1β and TGF-β1 within the tophus suggests that both pro- and anti-inflammatory factors present within the same lesion contribute to a cycle of chronic inflammation, attempted resolution and tissue remodeling.
Table: Summary of all results. For all cells, numbers indicate median (interquartile range) number of cells/high power field (at x20 magnification).
| | Fibrovascular zone
| p
|
Macrophage (CD68) | 55 (22.5-83) | 10 (3.5-16) | <0.0001 |
CD68+ multinucleated cells | 8 (5-38) | 0 (0-1) | <0.0001 |
Mast cell | 24 (16-36) | 18.5 (13-25.5) | 0.38 |
Neutrophil | 0.5 (0-2) | 0 (0-2) | <0.0001 |
|
|
|
|
T cell | 14 (6-32) | 8 (4-24) | 0.41 |
CD8+ T cell | 9 (7-34) | 18 (5-33) | 0.74 |
Plasma cell | 73 (36-113.5) | 15 (6.5-40.5) | <0.0001 |
CD20+ B cell | 0 (0-3) | 8 (4-19) | 0.0003 |
|
|
|
|
IL-1β | 169 (139-228) | 26 (21-34) | <0.0001 |
TGF-β1 | 27 (16-38.5) | 7 (4-18.5) | 0.035 |
Disclosure: N. Dalbeth, None; B. Pool, None; G. Gamble, None; T. Smith, None; K. E. Callon, None; F. M. McQueen, None; J. Cornish, None.