Clinical significance of serum and vitreous soluble interleukin-2 receptor in patients with intraocular lymphoma

Serum sIL-2R has been found to be elevated in most types of hematopoietic malignancies, including Hodgkin’s and non-Hodgkin’s lymphomas [13]. As clinical manifestations in malignant lymphoma may mimic a wide variety of diseases, the differential diagnosis of inflammatory disease is crucial in patients presenting with inflammatory symptoms. Several reports have evaluated serum sIL-2R values for the differential diagnosis of lymphoma from other conditions in the clinical setting [13,14,15].

IOL is a masquerade syndrome that mimics uveitis, making it difficult to diagnose correctly, especially in patients with marked vitreous haze, which is a common ocular finding seen in both IOL and uveitis. However, the clinical usefulness of serum sIL-2R in differentiating between IOL and uveitis remains unclear. The present study showed that serum sIL-2R was significantly higher in the uveitis group than in the IOL group. Only 20% of patients in the IOL group showed elevated serum sIL-2R, whereas 66.7% of patients in the uveitis group showed an elevation. Although serum sIL-2R is a reliable biomarker for the diagnosis of systemic lymphoma, these results indicates that serum sIL-2R cannot be a biomarker for diagnosis of IOL.

In contrast, although there was no significant difference, vitreous sIL-2R in the IOL group tended to be higher than in the uveitis group. Takeda et al. also reported that vitreous sIL-2R was significantly higher in IOL patients than in uveitis or epiretinal membrane (negative control) patients [19]. These results suggest that sIL-2R may be secreted from the intraocular tissues, and concentrated in the vitreous cavity along with the growth of IOL; however, the amount of sIL-2R leaking out to the serum from the vitreous cavity is too small to increase the level of serum sIL-2R.

The result that the serum sIL-2R level was significantly lower in the IOL group than in the uveitis group needs to be carefully considered. The uveitis patients enrolled in the study were not uveitis patients with common causes, but the idiopathic uveitis patients sufficiently presenting severe vitreous haze to suspect IOL. After IOL was ruled out pathologically, most of the patients might have had ocular sarcoidosis but did not meet the diagnostic criteria of sarcoidosis, even with systemic examinations, and were eventually diagnosed with idiopathic uveitis. We previously reported that the elevation of serum sIL-2R was seen in 25% of IOL patients, 76.4% of ocular sarcoidosis patients, and 5.6% of other uveitis patients [20]. In addition, previous reports have indicated the sensitivity and the specificity of serum sIL-2R levels were 81–98% and 91–99%, respectively, in the diagnosis of ocular sarcoidosis [13,14,15]. According to the results of these reports, elevated serum sIL-2R is a useful marker for ocular sarcoidosis but not for other uveitis [20,21,22,23]. It is unclear why serum sIL-2R was elevated in the uveitis patients in this study. They might have included some ocular sarcoidosis patients who had not been diagnosed yet.

MMP-2 and MMP-9, gelatinases which are capable of degrading type IV collagen, are known to be activated in lymphomas, and their activation is considered to be related to the metastasis of lymphomas [24,25,26]. We previously showed that the expression of MMP-2 in enucleated eyes and the cell blocks of vitreous samples was significantly higher in secondary IOL than in primary IOL [27]. Similarly, in this study, vitreous MMP-2 was significantly higher and MMP-9 also tended to be high in lymphoma patients with extraocular involvement. These results suggest that the population of lymphoma cells expressing high levels of MMP-2 and MMP-9 among the lymphoma cells with extraocular involvement may have a potentially high metastatic capability to reach the ocular tissue. The elevated levels of vitreous sIL-2R may be the result of the cleavage of IL-2R on the surface of T cells and B cell lymphoma cells with activated MMP-2 and MMP-9.

It has been reported that MMPs enabled T cells to pass through basement membranes by proteolytical cleaving, and that the inhibition of MMP activity was an efficient way to reduce inflammation in uveitis [28, 29]. Vitreous MMP-2 levels were not elevated in either the IOL and uveitis groups in this study, whereas vitreous MMP-9 levels in the uveitis group were significantly higher than in the IOL group. Although the mechanism of sIL-2R elevation in uveitis is still unknown, MMP-2 and MMP-9 may be involved in the migration of lymphocytes in uveitis as well as IOL.

There are certain limitations to the present study. The idiopathic uveitis patients in this study had uveitis of unknown etiology but presenting vitreous haze so thick that IOL was suspected. Therefore, the data on idiopathic uveitis from this study may not be common in generally considered idiopathic uveitis. This may have affected increased serum sIL-2R levels in the uveitis group.

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