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Mucopolysaccharidoses (MPSs) are rare inherited lysosomal storage diseases (LSDs) caused by deficient activity in one of the enzymes responsible for glycosaminoglycans lysosomal degradation. MPS II is caused by pathogenic mutations in the IDS gene, leading to deficient activity of the enzyme iduronate-2-sulfatase, which causes dermatan and heparan sulfate storage in the lysosomes. In MPS VI, there is dermatan sulfate lysosomal accumulation due to pathogenic mutations in the ARSB gene, leading to arylsulfatase B deficiency. Alterations in the immune system of MPS mouse models have already been described, but data concerning MPSs patients is still scarce. Herein, we study different leukocyte populations in MPS II and VI disease patients. MPS VI, but not MPS II patients, have a decrease percentage of natural killer (NK) cells and monocytes when compared with controls. No alterations were identified in the percentage of T, invariant NKT, and B cells in both groups of MPS disease patients. However, we discovered alterations in the naïve versus memory status of both helper and cytotoxic T cells in MPS VI disease patients compared to control group. Indeed, MPS VI disease patients have a higher frequency of naïve T cells and, consequently, lower memory T cell frequency than control subjects. Altogether, these results reveal MPS VI disease-specific alterations in some leukocyte populations, suggesting that the type of substrate accumulated and/or enzyme deficiency in the lysosome may have a particular effect on the normal cellular composition of the immune system. [ABSTRACT FROM AUTHOR]

Mucopolysaccharidoses (MPSs) are rare inherited lysosomal storage diseases (LSDs) caused by deficient activity in one of the enzymes responsible for glycosaminoglycans lysosomal degradation. MPS II is caused by pathogenic mutations in the IDS gene, leading to deficient activity of the enzyme iduronate-2-sulfatase, which causes dermatan and heparan sulfate storage in the lysosomes. In MPS VI, there is dermatan sulfate lysosomal accumulation due to pathogenic mutations in the ARSB gene, leading to arylsulfatase B deficiency. Alterations in the immune system of MPS mouse models have already been described, but data concerning MPSs patients is still scarce. Herein, we study different leukocyte populations in MPS II and VI disease patients. MPS VI, but not MPS II patients, have a decrease percentage of natural killer (NK) cells and monocytes when compared with controls. No alterations were identified in the percentage of T, invariant NKT, and B cells in both groups of MPS disease patients. However, we discovered alterations in the naïve versus memory status of both helper and cytotoxic T cells in MPS VI disease patients compared to control group. Indeed, MPS VI disease patients have a higher frequency of naïve T cells and, consequently, lower memory T cell frequency than control subjects. Altogether, these results reveal MPS VI disease-specific alterations in some leukocyte populations, suggesting that the type of substrate accumulated and/or enzyme deficiency in the lysosome may have a particular effect on the normal cellular composition of the immune system.

Abstract: Chronic mucocutaneous candidiasis (CMC) is a group of heterogeneous disorders characterised by primary selective susceptibility to chronic, recurrent Candida infections. The genetic defect of one subgroup of CMC patients have been identified as mutations of the autoimmune regulator (AIRE) gene. Recent data implicated the AIRE gene in iNKT cell development, raising the possibility that iNKT cells may be important in defending against Candida infections. In this study, we enumerated the circulating iNKT frequency in 22 CMC patients (9 with AIRE gene mutations) and 25 healthy controls. We also examined the effect of Candida stimulation on iNKT cells in vitro. Our data demonstrated that peripheral iNKT cell frequency is significantly reduced in CMC patients compared to healthy controls, regardless of their AIRE gene mutation status. Direct stimulation with heat-inactivated whole Candida did not induce iNKT cell proliferation. Furthermore, circulating iNKT cell frequencies in some healthy controls were comparable to CMC patients. These observations suggest that iNKT cell deficiency is part of the CMC disease phenotype irrespective of the presence of AIRE gene mutations but does not appear to confer susceptibility to chronic Candida infections. We postulate that the reduced circulating iNKT cell frequency in CMC is a consequence rather than a cause of chronic Candida infections. [ABSTRACT FROM AUTHOR]

Abstract: Invariant natural killer T (iNKT) cells have evolved to recognize CD1d-presented lipid antigens and are known to play important roles during infection with bacterial, viral, protozoan, and fungal pathogens. The limited antigen specificity and reactivity to self- and foreign antigens distinguish iNKT cells from MHC-restricted T cells and bear similarity to innate-like lymphocytes, such as NK cells, γδ T cells, MZB and B1-B cells. This review summarizes how direct recognition of microbial lipids or synergistic stimulation by self-lipids and pro-inflammatory cytokines results in activation of these innate-like iNKT cell during infection. iNKT cell activation in the absence of foreign antigen recognition is unique for cells bearing TCRs and underscores that not only the function but also the activation mechanism of iNKT cells is innate-like, and distinct from adaptive T cells. The different pathways of activation endow iNKT cells with the ability to respond rapidly to a wide variety of infectious agents and to contribute effectively to the early immune response during infection. [Copyright &y& Elsevier]

Interleukin-12 (IL-12) is a key cytokine involved in regulating the balance between TH1 and TH2 cells by promoting TH1 response. A reduced capacity to produce this cytokine could lead to aberrant TH2 development. On the same aspect significant impact of IL-12 on invariant natural killer T (iNKT) cells was reported. Therefore, we examined the serum levels of IL-12 and the absolute number of peripheral blood iNKT cells from 37 children with controlled asthma and 11 normal controls (age-matched) and correlating these two parameters with clinical asthma severity and Pulmonary function tests (PFTs). A significant decrease of serum levels of IL-12 and peripheral iNKT cells was found in total asthmatic cases compared with normal controls. This significant decrease of IL-12 levels was observed in severe asthmatic patients compared with mild and moderate cases. Serum levels of IL-12 and the numbers of peripheral iNKT cells were positively correlated with PFTs in both total asthmatic groups and in children with severe persistent asthma. Inverse correlation was found between serum level of IL-12 and different degrees of asthma. Whereas the numbers of peripheral blood iNKT cells showed no significant difference between clinical asthma severities. Impaired IL-12 production in asthmatic children beside decreasing the number of peripheral blood iNKT cells could be considered as a key component in asthma pathogenesis and hence their therapeutic manipulation may be of help in asthma management. [ABSTRACT FROM AUTHOR]