Inflammatory Markers As Secondary Biomarkers

Among the most prevalent hypothetical constructs used in lysosomal storage disorders is that of inflammation as a mediator, either as causative or as consequent effect, of lipid storage material. A pathway common to all MPS disorders (originally to describe MPS VI and MPS VII) has been developed based on inflammatory reactivity of connective tissues correlated with metal-loproteinases in chondrocytes [33], but it is not a qualitative measure of severity or responsiveness to therapy. In GM1 gangliosidosis because it is known that neuronal apoptosis and abnormalities in the central nervous system are secondary to storage, assessment of inflammatory cerebrospinal fluid markers showed correlation with clinical course but were not responsive to therapeutic interventions [34]. However, in a mouse model of gangliosidoses that showed disease progression with increased inflammatory cells in the microglia, the difference in GM1 (Sandhoff disease) and GM2 gangliosidosis (Tay-Sachs and late-onset Tay-Sachs disease) models was the timing of the onset of clinical signs [35] , which is not always taken into consideration. Thus, while inflammation may be postulated to be either a primary or a secondary index of disease activity, not all markers meet the criteria of sensitivity or clinical relevance. Similarly, in an early study of Gaucher disease using macrophage-derived inflammatory markers, there were some cytokines that correlated with disease severity and clinical parameters, but the results were equivocal in many markers [36]. In a knock-out mouse model of types A and B of Niemann-Pick disease, the macrophage inflammatory cytokine MIP-1a was elevated in disease-specific sites and declined with therapy [37], but this marker cannot be disease - specific. On a global level, however, mouse models for the various lysosomal disorders have recently shown a connection between lipid storage in the endosome or lysosome and invariant natural killer T (iNKT)-cell function, indicative of thymic involvement, albeit these findings would conflict with the theory of elaboration of inflammatory markers in lysosomal storage disorders [38] .

Project Management Made Easy

Project Management Made Easy

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