Atherosclerosis is a chronic inflammatory disease of the arterial wall in which presentation of autoantigens by dendritic cells (DCs) leads to the activation of T cells. Anti-inflammatory cells like Tregs counterbalance inflammation in atherogenesis. In our study, human carotid plaque specimens were classified as stable (14) and unstable (15) according to established morphological criteria. Vessel specimens (n = 12) without any signs of atherosclerosis were used as controls. Immunohistochemical staining was performed to detect different types of DCs (S100, fascin, CD83, CD209, CD304, and CD123), proinflammatory T cells (CD3, CD4, CD8, and CD161), and anti-inflammatory Tregs (FoxP3). The following results were observed: in unstable lesions, significantly higher numbers of proinflammatory cells like DCs, T helper cells, cytotoxic T cells, and natural killer cells were detected compared to stable plaques. Additionally, there was a significantly higher expression of HLA-DR and more T cell activation (CD25, CD69) in unstable lesions. On the contrary, unstable lesions contained significantly lower numbers of Tregs. Furthermore, a significant inverse correlation between myeloid DCs and Tregs was shown. These data suggest an increased inflammatory state in vulnerable plaques resulting from an imbalance of the frequency of local pro- and anti-inflammatory immune cells.

Fabry disease (FD) is a multisystem lysosomal storage disorder caused by mutations in the GLA gene. The clinical significance of the mutation p.D313Y is still under debate. Retrospective chart analysis of clinical (neurological, cardiac, renal, and ophthalmological), genetic, and biochemical (lyso-globotriaosylsphingosine, lyso-Gb3; enzyme activity) data was performed in all our patients carrying the p.D313Y mutation. Fourteen patients from 5 families (10 female, 4 male; age range 10-51) were included. Symptoms and organ manifestations compatible with FD could be identified in 10 patients. Cerebrovascular events occurred in 4 females. Seven patients reported pain or acroparaesthesia. Cornea verticillata was found in 1 patient, mild retinal vascular tortuosity in 5 patients. Lyso-Gb3 was elevated in 2 females with cerebrovascular involvement. Classical cardiac, renal or skin manifestations could not be identified. The mutation p.D313Y in the GLA gene may lead to organ manifestations and elevation of the Fabry-specific biomarker lyso-Gb3. Neurological symptoms (stroke and pain) and ocular manifestations seem to be the leading findings. Annual routine visits are recommended for patients carrying the p.D313Y mutation. Enzyme replacement therapy might be considered in symptomatic patients.

Neuronal ceroid lipofuscinosis (NCL) type 1 (CLN1) is a neurodegenerative storage disorder caused by mutations in the gene encoding the lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1). CLN1 patients suffer from brain atrophy, mental and motor retardation, seizures, and retinal degeneration ultimately resulting in blindness. Here, we performed an in-depth analysis of the retinal phenotype of a PPT1-deficient mouse, an animal model of this condition. Reactive astrogliosis and microgliosis were evident in mutant retinas prior to the onset of retinal cell loss. Progressive accumulation of storage material, a pronounced dysregulation of various lysosomal proteins, and accumulation of sequestosome/p62-positive aggregates in the inner nuclear layer also preceded retinal degeneration. At advanced stages of the disease, the mutant retina was characterized by a significant loss of ganglion cells, rod and cone photoreceptor cells, and rod and cone bipolar cells. Results demonstrate that PPT1 dysfunction results in early-onset pathological alterations in the mutant retina, followed by a progressive degeneration of various retinal cell types at relatively late stages of the disease. Data will serve as a reference for future work aimed at developing therapeutic strategies for the treatment of retinal degeneration in CLN1 disease.

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