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Histiocytoses are inflammatory myeloid neoplasms often driven by somatic activating mutations in mitogen-activated protein kinase (MAPK) cascade genes. H syndrome is an inflammatory genetic disorder caused by germ line loss-of-function mutations in SLC29A3, encoding the lysosomal equilibrative nucleoside transporter 3 (ENT3). Patients with H syndrome are predisposed to develop histiocytosis, yet the mechanism is unclear. Here, through phenotypic, molecular, and functional analysis of primary cells from a cohort of patients with H syndrome, we reveal the molecular pathway leading to histiocytosis and inflammation in this genetic disorder. We show that loss of function of ENT3 activates nucleoside-sensing toll-like receptors (TLR) and downstream MAPK signaling, inducing cytokine secretion and inflammation. Importantly, MEK inhibitor therapy led to resolution of histiocytosis and inflammation in a patient with H syndrome. These results demonstrate a yet-unrecognized link between a defect in a lysosomal transporter and pathological activation of MAPK signaling, establishing a novel pathway leading to histiocytosis and inflammation., (© 2023 by The American Society of Hematology.)

Purpose: To demonstrate experimentally, by means of histological and histomorphometric examinations, the sclera and choroid degenerative alterations, which take place at an early stage due to a hypercholesterolemic diet., Methods: New Zealand rabbits were divided into two groups: CG (control group) of 6 rabbits (6 eyes) received a regular diet for 6 weeks; G1, of 12 rabbits (12 eyes), was first fed a 1% cholesterol diet (Sigma-Aldrich) for 2 weeks and then from the 14th day on a 0.5% cholesterol diet (Sigma-Aldrich). The eyes underwent a histological analysis, stained with hematoxiline-eosine, and a morphometric examination. The histomorphometric analysis was performed in the posterior region, adjacent to the optic disk, and in the peripheral region., Results: The CG presented a mean sclera and choroid thickness of 228.61 +/- 31.71 micrometers in the peripheral region, while the thickness in the posterior region was approximately 246.07 +/- 25.66 micrometers. In G1, these values were 303.56 +/- 44.21 micrometers in the peripheral region and 295.59 +/- 62.59 in the posterior region. There was a statistically significant difference in the sclera and choroid thickness between the groups in the peripheral region (p<0.001); however, this difference did not occur in the posterior region (p=0.250). The large number of histiocytes and collagen fibers accounted for the increase of G1 wall thickness in relation to CG., Conclusion: This study demonstrated that the hypercholesterolemic diet in rabbits induces a fast increase in the choroid and sclera thickness, mainly due to the increase in the number of histiocytes and collagen fibers.

Objective: First, to characterize the histologic features of corneal buttons taken from two patients with chronic active herpetic stromal keratitis. Both eyes had suffered frequent and prolonged viral epithelial recurrences despite topical and systemic antiviral therapy and developed uniquely rapid deposition of chalklike stromal deposits. Second, to determine the clinical outcome of surgical intervention in eyes with such a pattern of herpetic disease., Design: Patients received topical antiviral medication and 200 to 400 mg of acyclovir five times daily for 2 or 5 months until penetrating keratoplasty. They received tapered doses of acyclovir after surgery. Corneal buttons were evaluated with light microscopy and electron microscopy., Results: Light microscopy of the specimens revealed calcium in the area of the chalklike deposits and a few cocci in the deep stroma. Electron microscopy showed numerous herpetic viral particles at various stages of maturity, including completely enveloped organisms, in the basal cells and keratocytes, and a few cocci in basal cells. Apart from one minor recurrence of a dendritic ulcer, both patients were free of herpetic disease at 13 and 22 months, required little to no medication, and had clear grafts., Conclusions: Rapid calcium deposition in herpetic corneas may indicate disease of sufficient severity to warrant surgical intervention for removal of a stromal viral reservoir. Such intervention can stop further recurrences of keratitis that is poorly controlled by antiviral therapy. Such chronically diseased eyes may also harbor unsuspected bacterial infection.