The discovery of a causative gene mutation (abnormal expansion of the CAG repeat in DRPLA gene) triggered the development of novel neuropathology in DRPLA, which has suggested that LDE225 concentration polyglutamine-related pathogenesis involves a wide range of central nervous system regions far beyond the systems previously reported to be affected. It is now likely that DRPLA has an aspect of neuronal storage disorder and has multiple system

degeneration, the lesion distribution of which varies depending on the CAG repeat sizes in the causative gene. Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder and is now also known as one of the CAG repeat (polyglutamine) diseases. According to a review article of DRPLA by Kanazawa,1 the first case of hereditary DRPLA was reported by Titica and Bogaert in 1946,2 who described two patients in a single family. Their clinical features included progressive hemiballism with choreoathetosis cerebellar ataxia and dementia. Neuropathology of the one case disclosed a combined degeneration of the pallidoluysian and dentatorubral systems. In 1958, Smith et al. reported a sporadic case of DRPLA without a family history, who showed cerebellar ataxia with combined degeneration of the dentato-rubral and pallido-Luysian Barasertib mw systems.3 The study which

laid special emphasis on the heritability of DRPLA was started by Naito et al. in 1972.4 The authors reported two families suffering from progressive myoclonus epilepsy (PME) with autosomal dominant transmission. In 1976, Oyanagi et al. reported autopsy findings of eight patients with degenerative PME, and confirmed the combined

degeneration of the two systems as the pathology responsible for PME and other neurological symptoms.5 It is interesting that the two sporadic patients in the study were later reclassified as myoclonus epilepsy with ragged-red fiber and essential myoclonus Rolziracetam and epilepsy. In 1982, Naito and Oyanagi proposed the name “hereditary dentatorubral-pallidoluysian atrophy” for the disease conditions characterized by the following features: (i) myoclonus epilepsy syndrome with or without cerebellar ataxia or choreoathetosis or both; (ii) dentatorubral-pallidoluysian atrophy; and (iii) autosomal dominant heredity.6 Dentatorubral-pallidoluysian atrophy patients show various symptoms, such as myoclonus, epilepsy, ataxia, choreoathetosis and dementia, and the combinations of these symptoms are determined by the age at onset.7 Patients with earlier onset (generally below the age of 20 years) show progressive myoclonus, epilepsy and mental retardation (juvenile type). Epileptic seizures are a feature in all patients with onset before the age of 20, and the frequency of seizures decreases with age after 20.

We apologize to our colleagues whose work was not cited here due to space limitations. Work on the inflammasome and NLR proteins in our laboratory is supported by grants from the Canadian Institutes for Health Research Selleckchem BAY 73-4506 (CIHR). M. S. is a CIHR New Investigator and a Burroughs

Wellcome Fund Investigator. Conflict of interest: The authors declare no financial or commercial conflict of interest. See accompanying Viewpoint: http://dx.doi.org/10.1002/eji.200940191 “
“This chapter contains sections titled: Introduction What is a mucosal tissue? Immune defence at mucosal tissue is multi-layered Origins of mucosal associated lymphoid tissue Concept of the common mucosal immune system How do T and B lymphocytes migrate into mucosal tissues? Special selleck kinase inhibitor features of mucosal epithelium Toll-like receptors and NOD proteins in the mucosa Antigen sampling at mucosal surfaces Mucosal dendritic cells Secretory dimeric IgA at mucosal

surfaces Regulation of J-chain and secretory component expression How does the sub-mucosa differ from the epithelium? Organized lymphoid tissue of the mucosa Cytokines in the mucosa Pathogens that enter via mucosal sites Immune diseases of mucosal tissues Summary “
“Down syndrome (DS) is the most common genetic disease and presents with cognitive impairment, cardiac and gastrointestinal abnormalities, in addition to other miscellaneous clinical conditions. DS individuals may have a high frequency of infections, usually of the upper respiratory tract, characterized by increased severity and prolonged course of disease, which are partially attributed to defects of the immune system. The abnormalities of the immune system associated with DS Calpain include: mild to moderate T and B cell lymphopenia, with marked decrease of naive lymphocytes, impaired mitogen-induced T cell proliferation, reduced specific antibody responses to immunizations and defects of neutrophil chemotaxis. Limited evidence of genetic abnormalities secondary to trisomy of chromosome 21 and affecting the immune system is available, such as the potential consequences of gene over-expression, most significantly

SOD1 and RCAN1. Secondary immunodeficiency due to metabolic or nutritional factors in DS, particularly zinc deficiency, has been postulated. Non-immunological factors, including abnormal anatomical structures (e.g. small ear canal, tracheomalacia) and gastro-oesophageal reflux, may play a role in the increased frequency of respiratory tract infections. The molecular mechanisms leading to the immune defects observed in DS individuals and the contribution of these immunological abnormalities to the increased risk of infections require further investigation. Addressing immunological and non-immunological factors involved in the pathogenesis of infectious diseases may reduce the susceptibility to infections in DS subjects.

20 Moreover the histamine receptor expression pattern is similar to what is known for other DC subtypes, such as MoDC.15 The newly described H4R is of particular interest in inflammatory

skin diseases21 and immunomodulatory effects on DC were already identified so we decided to study this receptor in more detail. By flow cytometry we could show that slanDC express the H4R on the protein level and that the expression level does not change during culture of the cells. We did not observe differences in the basal H4R expression level in diseases like AD and psoriasis, but the Th1-associated cytokine IFN-γ led to an up-regulation of H4R expression of slanDC isolated from patients with AD, whereas in healthy and psoriatic cells no difference was observed. The Th2-associated cytokine IL-13 and the toll-like receptor see more ligand poly this website I:C could not significantly modulate the expression of H4R in any of the studied groups. The increase of H4R expression upon IFN-γ stimulation was also described

for inflammatory dendritic epidermal cells,16 a subset of DC only present in the inflamed skin of AD patients.22 In chronic lesions of AD, predominantly IFN-γ and other Th1 cytokines are present, therefore it is likely that slanDC up-regulate the expression of the H4R during and after the infiltration to these tissues. Interestingly we did not find up-regulation of the H4R on slanDC derived from psoriasis patients, although this disease is also

Th1-mediated. Possible explanations for this observation could be disease-dependent differences in IFN-γ-mediated signalling or variations in the expression density of IFN-γ receptors. It has been shown for example that atopic diseases are associated with genetic polymorphisms in the IFN-γ receptor 1 gene leading to higher transcription of this receptor.23 To study the functional effects of histamine on slanDC, we stimulated PBMC as well as isolated slanDC with histamine and H4R agonists. After histamine stimulation we observed impaired intracellular production and release into the supernatant 4��8C of the pro-inflammatory cytokines TNF-α and IL-12 in response to slanDC activation by the toll-like receptor agonist LPS. Although the down-regulation of TNF-α was solely mediated via the H4R, we observed a dual H2R and H4R mediated effect for IL-12, which is in accordance with previous findings on MoDC.15 These observations strongly suggest that histamine impairs the pro-inflammatory capacity of slanDC, because the key cytokines of early immune responses are no longer produced in high amounts. Interleukin-12 is an important activator of natural killer cells and induces the differentiation of CD4+ T cells into Th1 cells. TNF-α belongs to the family of acute-phase proteins and is known to induce inflammation and apoptosis, to lead to vasodilatation and increased vascular permeability and to be a potent activator of endothelial cells.

5–300 ng/mL), thus being most reliably measurable. Both pro-inflammatory (TNF, IFN-γ, IL-6, IL-8, GM-CSF) and anti-inflammatory cytokines (TARC,

M-CSF) were highest in vesicular-dominated fractions. Not surprising, leucocyte (PMN) counts correlated with the relative levels of TNF, IL-6 and CXCL8 (ex-IL-8) but not with those of TGFβ1-3. Consequently, phosphatase inhibitor library anti-inflammatory and tolerance-related cytokines (IL-10, LIF, M-CSF), but not of TGFβ1-3, dominated in samples with few leucocytes, being their relative concentration lowest in leucocytic samples (>1 million/mL). These preliminary results suggest differences in cytokine/chemokine levels among fractions of the human ejaculate, which might be related to specific signalling properties in vivo. The suggested functions of SP proteins include their involvement in several essential steps preceding fertilization, such as regulating capacitation, establishment of the oviductal sperm reservoir, modulation of the uterine immune response and sperm transport in the female genital tract, as well as in gamete interaction and fusion.42 Interestingly, individual proteins from the same family appear to function in a species-specific Roxadustat manner. Differences in their structure, relative abundance and patterns of expression appear to determine species-specific effects of homologous

proteins.31 SP proteins differ somewhat in functionality related to their source, more clearly seen when fractionated ejaculates

are examined. Following mating or intercourse, mammalian spermatozoa are transported from the site of deposition towards the oviduct within minutes, owing to the concerted motility of the female tract muscle.72 These spermatozoa bathe, in individuals with fractionated ejaculation, in different fluids, such as the epididymal cauda fluid and the accessory gland secretion that is verted at the time the corresponding spurt of ejaculation is issued. As mentioned Methisazone before, the secretion of the first spurts of the sperm-rich fraction is acidic, and sperm proteins demonstrated to link themselves to acidic polysaccharides such as those in the secretion of the cervix, uterus and even oviduct.8 On the other hand, binding of some SP proteins, at least in the bull and stallion, inhibits such interaction of sperm proteins with acidic polysaccharides.73 SP proteins affect differentially sperm survival post-ejaculation, and those present in the last ejaculate fractions (seminal vesicle origin) have a more pronounced negative effect, perhaps in relation to the extensive presence of several proteins. For instance, cleavage products of the human ejaculate coagulum (basically vesicular secretion) inhibit sperm motility, which indicates those spermatozoa might be in disadvantage in vivo. The primary secretion in the first spurts, however, where spermatozoa are present, promotes longer sperm survival in humans16 and boars.

Figure 5A shows that the S297A variant translocated to the plasma membrane more efficiently than the WT counterpart. Quantification of the microscopic images using ImageJ (lower panel) confirmed that the enhanced recruitment of 14-3-3γ-bindingless Syk remained constant for at least 15 min after BCR ligation. The data are consistent with the results from our reverse selleck chemical interactome analysis of

the S297A mutant (see above) and strongly suggest that 14-3-3γ inhibits stimulation-dependent membrane recruitment of Syk. To address whether 14-3-3γ also controls the degree and kinetics of Syk activation we immunoprecipitated WT and mutant Syk from resting and stimulated B cells and subjected the obtained proteins to anti-phosphotyrosine

immunoblotting MS-275 research buy (Fig. 5B). Inactivation of the 14-3-3γ-binding site caused a marked increase in Syk phosphorylation 2 and 5 min after BCR ligation (compare lanes 3–4 with 8–9). Quantification of the signal intensities revealed an approx. 40% amplification of Syk phosphorylation at these time points of BCR stimulation (lower panel). In summary, phosphorylation of S297 and the accompanied recruitment of 14-3-3γ dampen the efficiency with which Syk translocates to the plasma membrane upon BCR activation, thereby limiting phosphorylation-induced Syk activation and subsequent triggering of downstream effector pathways. These findings are not restricted to DT40 B cells as Syk also co-immunoprecipitated with 14-3-3γ in BCR-activated DG75 human B cells, which showed robust GPX6 phosphorylation of the mode 1 binding motif (Fig. 6A, upper and middle panels, respectively). Note that maximal association between Syk and 14-3-3γ is observed in both cell lines after 5 min of BCR stimulation, which is consistent with the phosphorylation kinetics of S297. Similarly, we confirmed the increased membrane translocation of S297A mutant Syk in DG75 B cells (Fig. 6B). Owing to the endogenously expressed Syk in those

transfectants, their BCR-induced Ca2+ mobilization was normal as expected (data not shown). Taken together, the inhibitory complex between Syk and 14-3-3γ operates in chicken and human B cells. Understanding the diverse functions of Syk during development, activation and neoplastic transformation of hematopoietic cells requires comprehensive knowledge about its regulation by phosphorylation and the identity of Syk ligands. We have now determined the phosphorylation profile and the interactome of Syk in B cells. This was accomplished by affinity purification of Syk from SILAC-labeled resting or activated B cells followed by quantitative LC-MS/MS analysis of Syk phosphopeptides and Syk ligands. The B-lymphoid Syk phosphotome encompasses 32 acceptor sites with a strong prevalence for tyrosine residues (15) followed by serine (11) and threonine (6). More than 25 distinct Syk ligands were identified and most of these interactors required BCR activation.

In conclusion, the difference in therapeutic effect between LGG wild-type and dltD mutant in vivo suggests a role for the cell surface of the wild-type LGG strain in determining its therapeutic efficacy. Interestingly, these results with the

LGG dltD mutant show the potential of modifying the cell surface of probiotic strains for better treatment of IBD with probiotics. Combining these modified probiotic strains with the concept of ‘designer probiotics’[62] seems to be appealing for the future. One example of such a ‘designed’ strain is the IL-10-secreting Lactococcus lactis strain that shows potential in treatment of IBD [63,64]. Further in vitro studies are required to reveal the molecular mechanisms underlying the beneficial effects of this altered cell surface.

I.C. holds a PhD grant of the Kinase Inhibitor Library clinical trial Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT–Vlaanderen). D.B. holds a senior researcher grant of FWO–Vlaanderen. Additionally, this work was supported partially by the FWO–Vlaanderen through project G.0236·07. We thank K. Geboes for helpful KPT-330 mouse discussions regarding the set-up of the animal experiments. The authors also gratefully acknowledge L. Ophalvens for excellent technical assistance. We thank the anonymous reviewers for their helpful comments and suggestions. The authors declare no conflicts of interest. “
“The Melan-A/MART-126-35 antigenic peptide is one of the best studied human tumor-associated antigens. It is expressed in healthy melanocytes and malignant melanoma and is recognized by CD8+ T cells in the context of the MHC class I molecule HLA-A*0201. While an unusually large repertoire of CD8+ T cells specific for this antigen has been documented, the reasons for its generation have remained

elusive. In this issue of the European Journal of Immunology, Pinto et al. [Eur. J. Immunol. 2014. 44: 2811–2821] uncover one important mechanism Farnesyltransferase by comparing the thymic expression of the Melan-A gene to that in the melanocyte lineage. This study shows that medullary thymic epithelial cells (mTECs) dominantly express a truncated Melan-A transcript, the product of misinitiation of transcription. Consequently, the protein product in mTECs lacks the immunodominant epitope spanning residues 26–35, thus precluding central tolerance to this antigen. In contrast, melanocytes and melanoma tumor cells express almost exclusively the full-length Melan-A transcript, thus providing the target antigen for efficient recognition by HLA-A2-restricted CD8+ T cells. The frequency of these alternative gene transcription modes may be more common than previously appreciated and may represent an important factor modulating the efficiency of central tolerance induction in the thymus.

[14-16] Bongkrekic acid is a highly unsaturated tricarboxylic fatty acid, which inhibits oxidative phosphorylation by blocking the mitochondrial adenine nucleotide translocator.[15] Recently, the biosynthesis of the deadly toxin catalysed by an unusual polyketide synthase (PKS) was elucidated allowing for a better understanding of the pathogenicity of the contaminating bacteria.[17, 18] Besides bongkrekic acid, B. gladioli pv. cocovenenans is also known to produce the azapteridine toxoflavin (2), which might as well contribute to the toxic properties of contaminated tempe bongkrek.[19] Several recent studies indicated that Burkholderia

species are prolific producers of secondary metabolites with potent biological and pharmacological selleck chemicals properties.[20-28] Interestingly, some species were also found to be associated with mucoralean fungi and are of eminent metabolic importance for the fungi.[4,

29] A prominent example are the bacterial endosymbionts of R. microsporus.[30] The bacteria, Burkholderia rhizoxinica,[31] are producers of highly active antitumoural agents as well as a strong hepatotoxin.[32, 33] The discovery of these natural products is of importance as R. microsporus is not only a plant pathogen but also implicated with human infections.[6] In this regard it should be noted that full genome sequencing of natural product producing www.selleckchem.com/products/Nolvadex.html bacteria indicated that their biosynthetic potential may even be much higher than expected.[34] It is believed that the majority of secondary metabolite encoding Aldehyde dehydrogenase genes is only expressed under certain conditions and may require a specific trigger.[35] To get an overview of the secondary metabolic capabilities

of the toxinogenic B. gladioli strain and to investigate its metabolic contribution to the bacterial–fungal interaction, we performed a systematic survey on its biosynthetic potential on a genomic and an analytical-chemical level. Here, we report the formation and the biosynthesis of a class of antibiotics previously not known to be produced by these fungus-associated bacteria. We also describe the context-dependent production of the antibiotics and of the toxin bongkrekic acid in the fungal–bacterial coculture. Rhizopus microsporus var. oligosporus HKI 0401 (CBS 337.62; ATCC 46348; NRRL514) and Burkholderia gladioli pv. cocovenenans HKI 10521 (DSM 11318; ATCC 33664) were grown on potato dextrose agar (PDA) at 30 °C. Genomic DNA of B. gladioli was isolated using the MasterPure™ DNA purification kit (Epicentre Biotechnologies, Hessisch Oldendorf, Germany) to perform 454 Shotgun sequencing combined with a 3 kb paired end library. An approximately 25-fold coverage including 10 scaffolds was obtained and subsequent correct assembly of the generated contigs were achieved using the Lasergene SeqMan software (DNA Star, Inc., Madison, WI, USA).

4). In support of this, we found that the treatment of BCG-vaccinated mice with COX2 inhibitor in vivo significantly reduced Ag85B-specific Th17-cell responses (Fig.

4G), but not Ag85B-specific Th1-cell responses (Fig. 4H) or vaccine-induced protection in the lung following M. tuberculosis challenge (Fig. 4I). These data suggest that both in vivo and in vitro, blocking PGE2 results in reduced Th17-cell responses. Importantly, despite reduced Th17-cell responses, a competent Th1-cell response is generated, likely due to coincident loss of IL-10 production that can confer Tamoxifen ic50 vaccine-induced protection. These data suggest a role for IL-17 specifically to overcome IL-10 inhibitory effects. Consistent with a role for IL-17 in the induction of IL-12 in DCs 12, 13, we found that IL-17 treatment of BCG-exposed DCs enhanced IL-12 (Fig. 5A). Importantly, the treatment of IL-17 significantly decreased BCG-induced IL-10 production in DCs

(Fig. 5B). These data suggest that BCG exposure results in the induction of PGE2 and high levels of IL-10 that initially inhibits IL-12 production and Th1-cell BGB324 manufacturer responses in vivo (Fig. 2). Accordingly, the peak of PGE2 induction in vivo following BCG vaccination was at day 4, with significantly lower levels of PGE2 at later time points (Fig. 5C). However, BCG-induced PGE2 also mediates IL-23 induction and drives subsequent Th17-cell responses. IL-17 then induces IL-12 production and inhibits IL-10 production and mediates IFN-γ responses at later time points. Therefore, IFN-γ protein expression was not detected early, but

at later time points following BCG vaccination in vivo (Fig. 5D). In order to confirm that PGE-dependent IL-17 mediates Th1-cell responses to overcome BCG-mediated IL-10 inhibition, we depleted IL-17 in il10−/− BCG-vaccinated mice and measured Ag85B-specific Th1-cell responses in DLNs. Our data show that the depletion of IL-17 in B6 mice resulted in decreased Ag85B-specific Th1-cell response (Fig. 5E). However, depletion of IL-17 in il10−/− mice click here did not result in decreased Ag85B-specific Th1-cell responses when compared with il-10−/− BCG-vaccinated mice treated with isotype control antibody (Fig. 5E). These data suggest that IL-17 responses are required to drive Th1-cell responses, specifically to overcome IL-10-dependent Th1-cell inhibitory effects. PGE2 is critical for the induction of IL-23 responses and Th17-cell responses 18, 19, while inhibiting IL-12 responses through the production of IL-10 16. However, since PGE2-matured DCs can effectively induce IFN-γ-producing T cells 29, 30, we show that the immune system has developed means of counteracting the PGE2-mediated suppression of Th1-cell immunity. In this article, we show that the role for mycobacteria-induced PGE 2 is bifunctional since it not only induces IL-10 and limits early Th1-cell response, but also simultaneously induces IL-23 and subsequent IL-17 responses.

The supersaturation of extracellular fluids with

respect to calcium and phosphate has demanded the evolution of mechanisms to counteract and inhibit ectopic deposition MI-503 supplier of mineral outside bone. The propensity to pathological calcification is thus governed by the balance between factors promoting or inhibiting this process. The phospho-glycoprotein fetuin-A (Fet-A) is a key systemic mineral chaperone and inhibitor of soft-tissue and vascular calcification.[5] Fet-A is synthesized mainly in the liver where it is glycosylated and secreted into plasma, circulating at relatively high concentrations. Fet-A knockout mice show a variety of problems associated with ectopic mineral deposition and abnormal (but

not absent) bone development, together with metabolic complications depending on the model.[6-8] In patients with chronic kidney disease (CKD), Fet-A deficiency has been associated with increased arterial calcification scores and higher mortality rates.[9-11] However, data on serum total Fet-A concentrations RXDX-106 order are difficult to interpret because of analytical issues and conflicting data.[12, 13] Recent investigation suggests a more complicated and dynamic control system for this protein. In concert with other acidic serum proteins, Fet-A mediates the formation and stabilization of high molecular weight colloidal complexes of calcium phosphate mineral termed calciprotein particles (CPP).[14] Analogous to the way in which apoplipoproteins surround and solubilize their lipid cargo, those CPP provide a pathway for the transport of mineral nanocrystals and their clearance from the circulation by the mononuclear phagocytic system.[15] Previous work in rats suggests that CPP may originate

from the bone-remodelling compartment,[16] but they may also form spontaneously in other calcific micro-environments.[17-19] Circulating CPP burden can be inferred by assessing the apparent reduction serum Fet-A concentration (reduction ratio, RR) after high-speed centrifugation.[20] Inflammation has been identified as a key driver of ectopic mineralization.[21] Macrophage-derived pro-inflammatory cytokines such as interleukin-1α, interleukin-6, tumour necrosis factor-α and transforming growth factor-β have been shown to induce the transformation of vascular smooth muscle cells (VSMC) to a synthetic osteogenic phenotype. These osteochondrocytic-like VSMC extrude calcium phosphate crystal-laden matrix vesicles that nucleate mineralization of the vascular extracellular matrix.[22, 23] Importantly, calcium phosphate nanocrystals are themselves powerfully pro-inflammatory to macrophage, and themselves promote VSMC mineralization, potentiating a vicious cycle of inflammation and calcification.

To this purpose, innovative automated genome-based research technologies derived from recent knowledge of the human genome project may represent a valuable tool to weight the genetic/genomic influence on pharmacological outcomes, to assist clinicians to optimize daily therapeutic strategies (Fig. 1) and to identify more selective p38 MAPK assay and more appropriate targets for pharmacological interventions. For many years, several studies have emerged indicating that a substantial portion of variability in drug response is determined genetically. Approximately 40 years ago, Kalow and Gunn [14] described, for the first time, that subjects homozygous for a gene encoding for an atypical form

of the enzyme butyrylcholinesterase (pseudocholinesterase) were predisposed to develop a delayed recovery from muscular paralysis and prolonged apnoea after administration of the neuromuscular blocker succinylcholine. At almost the same time, it was observed that a common genetic variation in a phase II pathway of drug metabolism (N-acetylation) could result in striking differences in the half-life and plasma

concentrations of drugs metabolized by N-acetyltransferase. Such drugs included the anti-tuberculosis agent isionazid [15], the anti-hypertensive agent hydralazine [16] and the anti-arrhythmic drug procainamide [17]. In all cases these variations Cobimetinib cost had clinical consequences [18]. These early examples of potential influence of inheritance on drug effects, followed by subsequent studies, gave rise

to the field of ‘pharmacogenetics’. However, the molecular genetic basis for such inherited traits began to be elucidated only in the late 1980s, with the initial cloning and characterization of polymorphic human genes encoding for drug-metabolizing enzymes [19,20]. The use of different combinations of powerful drugs [e.g. calcineurin inhibitors, mammalian target of rapamycin (mTOR) inhibitors, corticosteroids] leads to a significant improvement in the treatment of several renal disorders and in the short- and long-term pharmacological management of Nabilone renal transplantation recipients [1,21]. However, these drugs are hampered frequently by a narrow therapeutic index. Moreover, these agents are characterized by a high variability in pharmacokinetic behaviour and by a poor correlation between drug concentrations and pharmocodynamic effects [22–24]. ‘Tailoring’ the dose of such drugs to the specific requirements of the individual patient to minimize toxicity while maintaining efficacy is therefore a challenging goal in clinical nephrology. To achieve this objective, several research programmes have been undertaken analysing the genetic influence on the patient’s response to these conventional treatments. Considerable evidence in the literature has reported that genetic polymorphisms have a major impact on the metabolism of azathioprine (AZA), a purine anti-metabolite used widely in nephrology [25–27].