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Human leukocyte antigens and Gaucher disease
... The Human Leukocyte Antigen (HLA) system is the Major Histocompatibility Complex (MHC) and a very polymorphic region of the genome in humans. The primary function of the HLA system is to regulate the immune response [5] and it has a big role in immunological reactions: about 100 diseases have already been associated with HLA system [6]. More specifically, the HLA complex appears to be important in the clinical expression of insulin dependent diabetes mellitus, Reiter's syndrome, especially HLA-B27 associated ankylosing spondylitis and HLA-DR4 with rheumatoid arthritis [6,7]. ...
... The primary function of the HLA system is to regulate the immune response [5] and it has a big role in immunological reactions: about 100 diseases have already been associated with HLA system [6]. More specifically, the HLA complex appears to be important in the clinical expression of insulin dependent diabetes mellitus, Reiter's syndrome, especially HLA-B27 associated ankylosing spondylitis and HLA-DR4 with rheumatoid arthritis [6,7]. It is also known that silicosis is associated with immunological reactions such as antinuclear antibody, rheumatoid factor, immune complexes, and raised immunoglobulin levels [8]. ...
Background: Denim sandblasting may cause silicosis as a result of free crystalline silica inhalation. Its pathogenesis remains unclear, but autoimmunity may play a role in the development of silicosis. The present study aimed to investigate the relationships between human leukocyte antigen (HLA) and the severity and latency period of silicosis. Methods: 48 silicotic patients in the Eastern part of Turkey were classified according to their latency period and disease severity. The distribution of HLAs according to disease severity and latency period was assessed. Results: A23 (7.5%), B49 (7.5%), and B51 (25%) were more common in the mild group than in the severe group, and B55 (8.9%) and DR4 (17.9%) were more common in the severe group than in the mild one. Only B51 was significantly more common in the mild group than in the severe one (25%, n = 10 vs. 7.1%, n = 4; p = 0.016). Conclusions: This study suggests that HLA antigens may play a particular role in the severity of silica-induced lung disease, but there was no association between HLA and progression time of the disease.
... The Human Leukocyte Antigen (HLA) system is the Major Histocompatibility Complex (MHC) and a very polymorphic region of the genome in humans. The primary function of the HLA system is to regulate the immune response [5] and it has a big role in immunological reactions: about 100 diseases have already been associated with HLA system [6]. More specifically, the HLA complex appears to be important in the clinical expression of insulin dependent diabetes mellitus, Reiter's syndrome, especially HLA-B27 associated ankylosing spondylitis and HLA-DR4 with rheumatoid arthritis [6,7]. ...
... The primary function of the HLA system is to regulate the immune response [5] and it has a big role in immunological reactions: about 100 diseases have already been associated with HLA system [6]. More specifically, the HLA complex appears to be important in the clinical expression of insulin dependent diabetes mellitus, Reiter's syndrome, especially HLA-B27 associated ankylosing spondylitis and HLA-DR4 with rheumatoid arthritis [6,7]. It is also known that silicosis is associated with immunological reactions such as antinuclear antibody, rheumatoid factor, immune complexes, and raised immunoglobulin levels [8]. ...
Denim sandblasting may cause silicosis as a result of free crystalline silica inhalation. Its pathogenesis remains unclear, but autoimmunity may play a role in the development of silicosis. The present study aimed to investigate the relationships between human leukocyte antigen (HLA) and the severity and latency period of silicosis.
48 silicotic patients in the Eastern part of Turkey were classified according to their latency period and disease severity. The distribution of HLAs according to disease severity and latency period was assessed.
A23 (7.5%), B49 (7.5%), and B51 (25%) were more common in the mild group than in the severe group, and B55 (8.9%) and DR4 (17.9%) were more common in the severe group than in the mild one. Only B51 was significantly more common in the mild group than in the severe one (25%, n = 10 vs. 7.1%, n = 4; p = 0.016).
This study suggests that HLA antigens may play a particular role in the severity of silica-induced lung disease, but there was no association between HLA and progression time of the disease.
... for GD patients showing MM. Putative explanation for these observations arises from the hypothesis of chronic stimulation of the immune system by Gaucher cells [8,9]. In fact, individuals with chronic inflammation are susceptible to develop MM as well as several lymphoproliferative disorders and malignancies [5]. ...
β2-Microglobulin is the major prognostic factor in multiple myeloma, a known comorbidity of Gaucher disease. We evaluated herein serum β2-microglobulin levels of 31 type 1 Gaucher patients; for 8/31 patients, pre- and post-treatment comparisons were made. Thirteen patients (on treatment = 6) had high levels of β2-microglobulin, and showed higher chitotriosidase activity and Severity Score Index, and lower concentration of platelets, than patients with normal levels. Levels of β2-microglobulin correlated with chitotriosidase activity (ρ = 0.65; p < 0.01), platelets (ρ = − 0.42; p = 0.02) and α1- (ρ = 0.43; p = 0.02) and α2-protein bands (ρ = − 0.40; p = 0.03). Regarding pre- and post-treatment values, median β2-microglobulin levels decreased after treatment (pre- = 2931 ng/mL; post- = 1970 ng/mL; p < 0.01). Our data suggest that levels of serum β2-microglobulin are frequently elevated in type 1 Gaucher patients, correlate with severity of the disease and decrease after treatment.
Objective:
To report on a novel HLA allele identified in a Chinese individual.
Methods:
Routine HLA genotyping was carried out with polymerase chain reaction-sequence specific oligonucleotide probes (PCR-SSOP) and sequencing-based typing (SBT).
Results:
A new HLA allele has been identified. The sequence differed from its closest allele B*37:04:01 at nt618 (GCG→GCA), which resulted in no change of codon 206.
Conclusion:
A novel HLA allele HLA-B*37:04:02 (GU391034) has been identified and officially named by the WHO Nomenclature Committee.
Gaucher disease, the most common lysosomal storage disease, is caused by a deficiency of glucocerebrosidase resulting in the impairment of glucosylceramide degradation. The hallmark of the disease is the presence of the Gaucher cell, a macrophage containing much of the stored glucosylceramide found in tissues, which is believed to cause many of the clinical manifestations of the disease. We have developed adult mice carrying the Gaucher disease L444P point mutation in the glucocerebrosidase (Gba) gene and exhibiting a partial enzyme deficiency. The mutant mice demonstrate multisystem inflammation, including evidence of B cell hyperproliferation, an aspect of the disease found in some patients. However, the mutant mice do not accumulate large amounts of glucosylceramide or exhibit classic Gaucher cells in tissues.
To clarify the influence of human leucocyte antigen B27 (HLA-B27) status on the phenotype of early axial spondyloarthritis (SpA).
708 patients with inflammatory back pain (IBP) defined by Calin or Berlin criteria were recruited; 654 fulfilled at least one of the SpA criteria (modified New York, European Spondyloarthropathy Study Group, Amor or Assessment of SpondyloArthritis international Society classification criteria for axial SpA) and were included in the analyses. Clinical, demographic and imaging parameters were compared between HLA-B27 positive and negative groups. Significant parameters in univariate differences between HLA-B27 positive and negative groups were retested in multivariate models explaining various outcomes.
Patients had a short duration of axial symptoms (mean 1.5 years) and HLA-B27 was present in 61.5%. In multivariate analysis, HLA-B27 positivity was associated with a younger age at onset of IBP (regression coefficient (B)=(-2.60), p<0.001), less delay in diagnosis (B=(-1.02), p=0.01), lower frequency of psoriasis (OR 0.59, p=0.01) and higher frequency of MRI inflammation of the sacroiliac joints (SIJ) (OR 2.13, p<0.001), MRI inflammation of the spine (OR 1.59, p=0.04) and radiographic sacroiliitis (OR 1.56, p=0.03). MRI inflammation of the SIJ was shown to be an intermediate variable between HLA-B27 positivity and radiographic sacroiliitis.
In early axial SpA, HLA-B27 is associated with earlier onset of IBP, less delay in diagnosis, axial inflammation (spine and SIJ), radiographic damage of the SIJ, decreased disease activity and lower frequency of psoriasis. It is not associated with physical function and MRI structural lesions of the SIJ.
Glucosylceramide lipidosis results from a defective lysosomal degradation of this glycolipid. Lipid degradation is controlled by two components, the enzyme beta-glucocerebrosidase and a sphingolipid activator protein. While most Gaucher cases are due to mutations within the gene that codes for the lysosomal enzyme, only two patients have been described with normal enzyme levels and mutations in the gene for the sphingolipid activator protein C (sap-C). Here we present the detailed neurological manifestations, neuropathological findings and brain lipid composition in one sap-C-deficient patient. The patient was an 8-year-old boy who presented with transient losses of consciousness, myoclonic jerks and generalized seizures resistant to all antiepileptic drugs. He developed progressive horizontal ophthalmoplegia, pyramidal and cerebellar signs, and died at the age of 15.5 years. Neuropathological studies demonstrated neuronal cell loss and neuronophagia, massive intraneuronal lipid storage and lack of perivascular Gaucher cells. Electron microscopy examination showed different types of storage including lipofuscin granules as well as the cytosomes with parallel arrays of bilayers that are assumed to be formed by stored lipids. General brain lipid composition did not show a remarkable increase or loss of any of the major lipid fractions but the glucosylceramide concentration in the cortex of several anatomical regions showed a striking increase. Fatty acid composition of the ceramide moiety clearly suggests that gangliosides are the main precursors in the cerebral cortex, while it implies an additional and distinct source in the cerebellum. Studying the phenotypic consequences of mutant sphingolipid activator proteins is critical to a better understanding of the physiological significance of these proteins.
Gaucher disease, the most common lysosomal storage disease, is caused by a deficiency of glucocerebrosidase resulting in the impairment of glucosylceramide degradation. The hallmark of the disease is the presence of the Gaucher cell, a macrophage containing much of the stored glucosylceramide found in tissues, which is believed to cause many of the clinical manifestations of the disease. We have developed adult mice carrying the Gaucher disease L444P point mutation in the glucocerebrosidase (Gba) gene and exhibiting a partial enzyme deficiency. The mutant mice demonstrate multisystem inflammation, including evidence of B cell hyperproliferation, an aspect of the disease found in some patients. However, the mutant mice do not accumulate large amounts of glucosylceramide or exhibit classic Gaucher cells in tissues.
Individuals with Gaucher disease vary significantly with regard to degree of bone disease, but there are no predictive markers for severity of skeletal involvement.
To determine the frequency of polymorphisms of interleukin-6 (IL-6) among patients with Gaucher disease, and the relationship to bone mineral density (BMD) and other markers of disease severity.
Case-control study.
Genotyping for the 174G --> C promoter polymorphism of IL-6 was performed in adult patients with Gaucher disease for whom there was concurrent bone mineral density (BMD) data and in healthy Ashkenazi Jewish controls.
The prevalence of allelic variants (58% G/G, 36% G/C, and 6% C/C) was similar in Ashkenazi Jewish adults with Gaucher disease as in Ashkenazi Jewish controls, but significantly different (p < 0.05) from that reported among Caucasians. No statistically significant correlation was found between IL-6 genotypes and BMD or markers of severity of Gaucher disease. Patients with the C/C genotype had relatively mild Gaucher disease.
The IL-6 polymorphisms appear to be distributed differently in Ashkenazi Jews than among other Caucasians. In Gaucher disease, the C/C genotype may be associated with a milder Gaucher phenotype, and may serve as a mitigating genetic modifier.
Non-neuronopathic (type 1) Gaucher's disease, a recessive disorder caused by glucocerebrosidase deficiency, shows marked variability in the severity and extent of clinical expression: many individuals who harbour two mutant alleles remain mildly affected or asymptomatic. Despite much effort, it is not possible accurately to predict disease severity from the genotype, or to identify those patients destined to develop severe disease and meriting early treatment.
To determine the degree to which variance in Gaucher disease is determined by non-heritable factors.
Case reports of monozygotic and dizygotic twin pairs.
For the monozygotic twin pair, homozygous for the frequent N370S glucocerebrosidase allele, there was no evidence that significant lipid storage was ever initiated in the unaffected twin. In contrast, pathological storage of glucocerebroside has been present in the macrophages of both members of the dizygotic twin pair (compound heterozygotes for the N370S and L444P alleles) from an early age but, by the age of 57 years, only one has developed symptoms.
Non-heritable factors influence Gaucher disease expression in genetically predisposed individuals. Understanding the interactions between heritable and non-heritable factors will be critical for an analysis of pathogenesis, and the treatment of individuals predisposed to Gaucher disease.
Luminex technology is a new flow cytometry technology enabling us to analyse numerous reactions in a unique tube or well. It is a multiplexed data acquisition and analysis platform of microsphere-based assays that performs simultaneous measurements of up to 100 different analytes. In the histo- compatibility field, individual sets of microspheres are modified with reactive components such as antigens in order to perform HLA antibodies identification, or with oligonucleotides in order to perform HLA typing after reverse PCR-SSO. Thus microspheres are the equivalent of a panel of HLA typed lymphocytes (for PRA determination and antibody identification) or equivalent to a large set of probes selected to assign HLA typing. This new tool can be very useful in HLA laboratories since it is very easy to use and the results are concordant with those obtained with reference technics.
Copyright John Libbey Eurotext 20003.
Although the existence of anti-inflammatory alternatively activated macrophages (aamphi) has been accepted widely based on in vitro studies, their in vivo location, phenotype, and function still are debated. Gaucher disease (GD) is caused by a genetic deficiency in the lysosomal enzyme glucocerebrosidase and is characterized by accumulation of glycosphingolipids in so-called Gaucher cells (GCs). By using immunohistochemical analysis, we investigated whether this results in an aamphi phenotype. GCs are macrophage-like cells, expressing acid phosphatase, CD68, CD14, and HLA class II, but not CD11b, CD40, or dendritic cell markers. GCs show infrequent immunoreactivity for mannose receptor GCs did not express proinflammatory cytokines such as tumor necrosis factor alpha and monocyte chemoattractant protein 1, but did express the aamphi markers CD163, CCL18, and interleukin-1 receptor antagonist. Furthermore, CD36 and signal receptor protein alpha, involved in lipid uptake, also were observed on GCs. Thus, GCs represent a distinctive population of myeloid cells that resemble aamphi but differ from previously described in vitro aamphi.
The human major histocompatibility (MHC) genomic region at chromosomal position 6p21 encodes the six classical transplantation HLA genes and many other genes that have important roles in the regulation of the immune system as well as in some fundamental cellular processes. This small segment of the human genome has been associated with more than 100 diseases, including common diseases--such as diabetes, rheumatoid arthritis, psoriasis, asthma and various autoimmune disorders. The MHC 3.6 Mb genomic sequence was first reported in 1999 with the annotation of 224 gene loci. The locus and allelic information of the MHC continue to be updated by identifying newly mapped expressed genes and pseudogenes based on comparative genomics, SNP analysis and cDNA projects. Since 1999, new innovations in bioinformatics and gene-specific functional databases and studies on the MHC genes have resulted in numerous changes to gene names and better ways to update and link the MHC gene symbols, names and sequences together with function, variation and disease associations. In this study, we present a brief overview of the MHC genomic structure and the recent information that we have gathered on the MHC gene loci via LocusLink at the National Centre for Biological Information (http://www.ncbi.nih.gov/.) and the MHC genes' association with various diseases taken from publications and records in public databases, such as the Online Mendelian Inheritance in Man and the Genetic Association Database.
We investigated HLA class II alleles in women with systemic sclerosis (SSc), a rare disease that preferentially affects women.
Specific alleles of DRB1, DQA1 and DQB1 were determined by DNA-based HLA typing for women with SSc (n = 102) and healthy women (n = 533). All study subjects were Caucasian. DRB1, DQA1 and DQB1 allele frequencies of women with SSc were compared with those of healthy women.
Among women with SSc, 29.4% (30/102) and among healthy women 10.7% (57/533) had DRB1*11. Allele frequencies were compared for women with SSc and healthy women (each woman has two alleles). The allele frequency of DRB1*11 was 15.7% (32/204 alleles) in SSc women and 5.8% (62/1066 alleles) in healthy women (P = 0.000002). The increase of DRB1*11 was found both in diffuse (P = 0.0001) and limited SSc (P = 0.002) (allele frequencies 15.0 and 17.2%, respectively). Among women with diffuse SSc, there was a disproportionate increase of the DRB1*1104 allele (P = 0.0004) with no increase of DRB1*1101 (P = 1.00). In contrast, in limited SSc the strongest association was with DRB1*1101 (P = 0.008), with a less significant increase of DRB1*1104 (P = 0.04).
An increase of DRB1*11 in SSc is consistent with other reports. Although present in both diffuse and limited SSc disease subsets, the increase was predominantly due to over-representation of DRB1*1104 in women with diffuse SSc. Women with limited SSc had a preponderance of DRB1*1101, the most common allele in healthy women. DRB1*1104 and DRB1*1101 differ by a single amino acid at position 86, where the former has valine and the latter glycine.
The major histocompatibility complex (MHC) is the most important region in the vertebrate genome with respect to infection and autoimmunity, and is crucial in adaptive and innate immunity. Decades of biomedical research have revealed many MHC genes that are duplicated, polymorphic and associated with more diseases than any other region of the human genome. The recent completion of several large-scale studies offers the opportunity to assimilate the latest data into an integrated gene map of the extended human MHC. Here, we present this map and review its content in relation to paralogy, polymorphism, immune function and disease.
Chronic hepatitis C virus (HCV) infection is associated with immunological abnormality, including circulating immune complexes, production of autoantibodies, and concurrent autoimmune disorders.1,2 Both viral and host factors may contribute to the development of autoantibodies and rheumatological manifestations. In this study we investigated the production of autoantibodies in patients with HCV in order to determine a possible link between the polymorphic HLA-DRB1 allele(s) and autoantibody production in chronic HCV infection.
We analysed HLA-DR polymorphisms in 288 HCV infected subjects in the Department of Internal Medicine, National Taiwan University Hospital. All patients were assayed for their serum autoantibodies with detection of antinuclear antibodies (ANA), rheumatoid factor (RF), antithyroid antibodies (antithyroglobulin (ATG) and antimicrosomal (AMG) antibodies), and antineutrophil cytoplasmic antibodies (ANCA). The HLA-DR polymorphisms were genotyped by polymerase chain reaction and sequence-specific …
Juvenile idiopathic arthritis (JIA) is the commonest rheumatic disease of childhood. Uveitis is the commonest eye complication of JIA, potentially leading to eye surgery and/or visual loss. JIA is a complex genetic trait with well-established HLA-DRB1 associations. The aim of this study was to investigate the involvement of HLA-DRB1 in JIA-associated uveitis.
A set of 130 UK Caucasian simplex families consisting of healthy parent(s) and a child affected with juvenile oligoarticular idiopathic arthritis (of which 31 had developed uveitis) had previously been screened for multiple markers in the major histocompatibility complex region. Associations with uveitis were investigated through haplotype pattern mining (HPM) and the extended transmission disequilibrium test (ETDT). A further set of 228 UK Caucasian patients with long-standing JIA were fully genotyped for HLA-DRB1 using PCR with sequence-specific primers. Associations of HLA-DRB1 alleles in patients with uveitis (n = 50) were examined individually using the chi 2 test.
In the first cohort, HPM identified significant associations of HLA-DRB1*13 with uveitis in juvenile oligoarthritis (P = 0.002). The ETDT confirmed overtransmission of this allele in the families (empirical global P = 0.018). In the second cohort, the significant association of uveitis with HLA-DRB1*13 was replicated (P = 0.0002, odds ratio 3.4, 95% confidence interval 1.7-6.5).
This study has established the HLA-DRB1*13 association with uveitis in JIA. Further work is necessary in order to explore the prognostic potential of this marker.
Hepatitis B (HBV) and hepatitis C (HCV) viral infection or co-infection leads to risk of development of chronic infection, cirrhosis and hepatocellular carcinoma (HCC). Immigration and globalization have added to the challenges of public health concerns regarding chronic HBV and HCV infections worldwide. The aim of this study is to review existing global literature across ethnic populations on HBV and HCV related human leukocyte antigen (HLA) associations in relation to susceptibility, viral persistence and treatment. Extensive literature search was conducted to explore the HLA associations in HBV and HCV infections reported across global populations over the past decade to understand the knowledge status, weaknesses and strengths of this information in different ethnic populations. HLA DR13 is consistently associated with HBV clearance globally. HLADRB1*11/*12 alleles and DQB1*0301 are associated with HBV persistence but with HCV clearance worldwide. Consistent association of DRB1*03 and *07 is observed with HCV susceptibility and non-responsiveness to HBV vaccination across the population. HLA DR13 is protective for vertical HBV and HCV transmission in Chinese and Italian neonates, but different alleles are associated with their susceptibility in these populations. HLA class I molecule interactions with Killer cell immunoglobulin like receptors (KIR) of natural killer (NK) cells modulate HCV infection outcome via regulating immune regulatory cells and molecules. HLA associations with HBV vaccination, interferon therapy in HBV and HCV, and with extra hepatic manifestations of viral hepatitis are also discussed. Systematic studies in compliance with global regulatory standards are required to identify the HLA specific viral epitope, stage specific T cell populations interacting with different HLA alleles during disease progression and viral clearance of chronic HBV or HCV infections among different ethnic populations. These studies would facilitate stage specific therapeutic strategies for clearance of HBV and HCV infections or co-infections across global populations and aid in identification of HBV-HCV combined vaccine. HLA associations of chronic HBV or HCV development with confounding host factors including alcohol, drug abuse, insulin resistance, age and gender are lacking and warrant detailed investigation across global populations.
Lysosomal storage disorders (LSDs) are genetically inherited diseases characterized by the accumulation of disease-specific biological materials such as proteolipids or metabolic intermediates within the lysosome. The lysosomal compartment's central importance to normal cellular function can be appreciated by examining the various pathologies that arise in LSDs. These disorders are invariably fatal, and many display profound neurological impairment that begins in childhood. However, recent studies have revealed that several LSDs also have irregularities in the function of the immune system. Gaucher disease, mucopolysaccharidosis VII, and alpha-mannosidosis are examples of a subset of LSD patients that are predisposed towards immune suppression. In contrast, GM2 gangliosidosis, globoid cell leukodystrophy, Niemann-Pick disease type C1 and juvenile neuronal ceroid lipofuscinosis are LSDs that are predisposed towards immune system hyperactivity. Antigen presentation and processing by dedicated antigen presenting cells (APCs), secretion of pore-forming perforins by cytotoxic-T lymphocytes, and release of pro-inflammatory mediators by mast cells are among the many crucial immune system functions in which the lysosome plays a central role. Although the relationship between the modification of the lysosomal compartment in LSDs and modulation of the immune system remains unknown, there is emerging evidence for early neuroimmune responses in a variety of LSDs. In this review we bridge biochemical studies on the lysosomal compartment's role in the immune system with clinical data on immune system irregularities in a subset of LSDs.
Gaucher disease is the most common lysosomal storage disease. It is caused by a deficiency in the lysosomal enzyme glucocerebrosidase, a β-glucosidase, which results in the accumulation of the lipid glucocerebroside in macrophages throughout the body. Gaucher disease is most common in the Ashkenazi Jewish population, and three mutations of the gene encoding glucocerebrosidase (GBA) have been shown to be prevalent in this population (c.1226 A > C [N370S], 84GG and IVS2[+1]). In non-Jewish patients, the most common mutation is c.1448 G > C (L444P). Until 15 years ago, treatment has been restricted to symptomatic interventions, such as splenectomy or hip replacement. However, there are now specific treatment options – enzyme replacement therapy and substrate reduction therapy. Future developments may include the use of chaperone therapy.
Conclusion: The lessons that we have learned from Gaucher disease may well be applicable to the development of therapies for some of the other less common lysosomal storage diseases.
We investigate the contribution of the Iberian bat fauna to the cryptic diversity in Europe using mitochondrial (cytb and ND1) and nuclear (RAG2) DNA sequences. For each of the 28 bat species known for Iberia, samples covering a wide geographic range within Spain were compared to samples from the rest of Europe. In this general screening, almost 20% of the Iberian species showed important mitochondrial discontinuities (K2P distance values > 5%) either within the Iberian or between Iberian and other European samples. Within Eptesicus serotinus and Myotis nattereri, levels of genetic divergence between lineages exceeded 16%, indicating that these taxa represent a complex of several biological species. Other well-differentiated lineages (K2P distances between 5–10%) appeared within Hypsugo savii, Pipistrellus kuhlii and Plecotus auritus, suggesting the existence of further cryptic diversity. Most unsuspected lineages seem restricted to Iberia, although two have crossed the Pyrenees to reach, at leas...
Context Lysosomal storage disorders represent a group of at
least 41 genetically distinct, biochemically related, inherited
diseases. Individually, these disorders are considered rare, although
high prevalence values have been reported in some populations. These
disorders are devastating for individuals and their families and result
in considerable use of resources from health care systems; however, the
magnitude of the problem is not well defined. To date, no comprehensive
study has been performed on the prevalence of these disorders as a
group.Objective To determine the prevalence of lysosomal storage
disorders individually and as a group in the Australian population.Design Retrospective case studies.Setting Australia, from January 1, 1980, through December 31,
1996.Main Outcome Measure Enzymatic diagnosis of a lysosomal storage
disorder.Results Twenty-seven different lysosomal storage disorders were
diagnosed in 545 individuals. The prevalence ranged from 1 per
57,000 live births for Gaucher disease to 1 per 4.2 million live
births for sialidosis. Eighteen of 27 disorders had more than 10
diagnosed cases. As a group of disorders, the combined prevalence was 1
per 7700 live births. There was no significant increase in the rate of
either clinical diagnoses or prenatal diagnoses of lysosomal storage
disorders during the study period.Conclusions Individually, lysosomal storage disorders are rare
genetic diseases. However, as a group, they are relatively common and
represent an important health problem in Australia.
Gaucher disease is a genetic disorder of sphingolipid metabolism resulting from dysfunction of the lysosomal membrane-associated glycoprotein glucocerebrosidase (GBA) and resulting in intracellular accumulation of glucosylceramide and other glycolipids. Although the gene defect and relevant biochemical pathways have been defined, the mechanisms by which substrate accumulation causes disease manifestations are not well understood. The direct effects of a build up of substrate laden cells may account for some aspects of disease but the overall pathology is likely to be more complex with effects of stored material on a variety of intra and extra cellular functions. In this article we review the GBA gene and its protein product, with associated defects, lipid metabolism and storage, enzyme misfolding and endoplasmic reticulum stress, calcium homeostasis, oxidative stress and autophagy and at each point examine how therapies that are currently available, in clinical development or at earlier stages of basic research might address the pathological mechanisms.
We describe monozygotic twin sisters, born to consanguineous Moroccan parents, who are highly discordant for the manifestations of Gaucher disease. Both carry Gaucher genotype N188S/N188S. One has severe visceral involvement, epilepsy, and a cerebellar syndrome. Her twin does not manifest any symptoms or signs of Gaucher disease but suffers from type 1 diabetes mellitus. The concurrence of a mild Gaucher mutation with a severe phenotype, as well as the occurrence of highly discordant phenotypes in a pair of monozygotic twins, is discussed.
In the course of histocompatibility typing in ankylosing spondylitis and Reiter's disease the B27 antigen (new terminology for W27) was found to have a lower frequency among black than among white patients. Seven patients with ankylosing spondylitis (all whites) also had Crohn's disease. There were no patients with ulcerative colitis or psoriasis. Surprisingly enough, virtually all five white B27 negative patients with ankylosing spondylitis are in the subgroup with Crohn's disease. The blacks with ankylosing spondylitis fall into two groups. Seven with severe disease, including disabling hip involvement, are positive for B27. Of eight with mild to moderate spondylitis, six are B27 negative).
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Eighty-eight Japanese patients with rheumatoid arthritis and 104 normal Japanese persons were typed for HLA A, B, C, and DR antigens. The frequency of HLA DR4 was 70.5% in patients compared with 46.1% in normal controls (P less than 0.001). However, a sex difference in the frequency of HLA DR4 in patients was noted. HLA DR4 was found in 80.6% of male patients, which was highly significant compared with controls (P less than 0.0005), while only a borderline increase of 60.5% was found in female patients (P less than 0.05). In addition, the frequency of HLA DR2 was remarkably low in male patients. These suggest the possible heterogeneity of rheumatoid arthritis in Japanese.
Concentrations of IgA, IgG, and IgM were measured in 25 patients with Gaucher's disease. The mean of each was significantly higher than that generally observed in healthy adults. A direct correlation was noted between IgA and IgG concentrations and age. Patients who underwent splenectomy had IgM concentrations significantly lower than those of persons who did not. In two of 25 patients, multiple myeloma of the nonsecretory type developed. The migration inhibition factor (MIF) test performed with the lymphocytes of our patients was positive to glucocerebroside in four of 17 patients, to glucocerebrosidase in four of 19 patients, and to the extracts of the spleen of a patient with Gaucher's disease in three of eight patients. The results of al MIF tests were negative in six control subjects with splenomegaly of other causes. Our results suggest that in Gaucher's disease there is chronic stimulation of the humoral immune system. The first expression of this stimulation is the production of polyclonal immunoglobulins and, in due time, the development of monoclonal immunoglobulin as well as multiple myeloma.
We have developed a single DNA typing method which uses 144 sequence-specific primer (SSP) reactions to simultaneously detect all known HLA-A, B, C, DRB1, DRB3, DRB4, DRB5 and DQB1 specificities in an allele specific or group specific manner using the same method, reagents, PCR parameters and protocols for all loci. The results from this integrated class I & II method can be visualized on a single photographic or electronic image and hence is described as "Phototyping". Phototyping has an overall resolution greater than or equivalent to good serology and results can be obtained in under 3 hours making the method suitable for genotyping potential cadaver donor peripheral blood without serological backup. This in turn produces the potential for reducing cold ischaemia times in renal transplantation as well as the application of prospective matching to cardiac and liver transplantation. The method has capacity to detect new alleles, for example, novel amplification patterns suggestive of 4 new HLA-B alleles have been detected. The Phototyping set has been used as the sole method of HLA typing for over 1010 individuals. Phototyping is not problem-free; deviations from the standard protocol, poor quality DNA and unsuitable PCR machines can result in individual PCR failures or in incorrect assignment of antigens. Approximately 5% of genotypes were repeated (either partially or fully) because of incomplete or equivocal results.
Lysosomal storage disorders represent a group of at least 41 genetically distinct, biochemically related, inherited diseases. Individually, these disorders are considered rare, although high prevalence values have been reported in some populations. These disorders are devastating for individuals and their families and result in considerable use of resources from health care systems; however, the magnitude of the problem is not well defined. To date, no comprehensive study has been performed on the prevalence of these disorders as a group.
To determine the prevalence of lysosomal storage disorders individually and as a group in the Australian population.
Retrospective case studies.
Australia, from January 1, 1980, through December 31, 1996.
Enzymatic diagnosis of a lysosomal storage disorder.
Twenty-seven different lysosomal storage disorders were diagnosed in 545 individuals. The prevalence ranged from 1 per 57000 live births for Gaucher disease to 1 per 4.2 million live births for sialidosis. Eighteen of 27 disorders had more than 10 diagnosed cases. As a group of disorders, the combined prevalence was 1 per 7700 live births. There was no significant increase in the rate of either clinical diagnoses or prenatal diagnoses of lysosomal storage disorders during the study period.
Individually, lysosomal storage disorders are rare genetic diseases. However, as a group, they are relatively common and represent an important health problem in Australia.
To identify HLA markers that may contribute to the genetic susceptibility of Koreans to psoriasis, we studied 84 psoriasis patients, with serologic HLA types of A, B, and genotypes of HLA-Cw, DRB1, DQA1, DQB1, DPB1 alleles. The distribution of HLA markers and the associated haplotypes were analyzed according to age and sex. HLA-Cw*0602 showed the strongest association with psoriasis (relative risk = 36.0, p < 10-8, Pc < 8 x 10-7). The frequencies of A1 (relative risk = 17.0, p < 9 x 10-7, Pc < 7 x 10-5), A30 (relative risk = 5.5, p < 2 x 10-5, Pc < 0.001), B13 (relative risk = 5.6, p < 4 x 10-6, Pc < 3 x 10-4), B37 (relative risk = 30.3, p < 7 x 10-7, Pc < 6 x 10-5), DRB1*07 (relative risk = 5.9, p < 2 x 10-6, Pc < 8 x 10-5), DRB1*10 (relative risk = 26.4, p < 4 x 10-6, Pc < 3 x 10-4), DQA1*02 (relative risk = 6.2, p < 5 x 10-7, Pc < 4 x 10-4), DQB1*02 (relative risk = 2.5, p < 0.005, Pc = ns) and DPB1*1701 (relative risk = 24.6, p < 9 x 10-6, Pc < 7 x 10-4) were also significantly increased in Korean psoriasis patients. Type I and type II psoriasis were subdivided into groups of below and above 30 y of age, because of the significant difference found in HLA-Cw*0602 phenotype frequency between the two groups (83.9% vs. 54.5%, p < 0. 009). In addition to HLA-Cw*0602, the frequencies of B37 and DPB1*1701 were significantly higher in type I as opposed to type II psoriasis. HLA-A30-B13-Cw*0602-DRB1*07-DQA1* 02-DQB1*02 was identified as a high risk haplotype. This was particularly true at an early age in the female. HLA-A33-B44-Cw*1401-DRB1*13-DQA1* 01-DQB1*06-DPB1*0401 was defined as a protective haplotype for psoriasis. The extended haplotype HLA-A1-B37-Cw*0602-DRB1*10-DQA1*01-DQB1*05 was discovered to be a high-risk factor in Koreans. To summarize, this study demonstrates the differential association of HLA according to sex, and identifies a newly found high-risk haplotype and a protective haplotype in Korean psoriasis patients.
An immunohistochemical study on bone marrow biopsies and spleens of patients with Gaucher's disease and chronic myeloid leukemia was performed to investigate the immunophenotype of Gaucher's cells and pseudo-Gaucher cells. A panel of antibodies was used which were reactive on paraffin-embedded tissues and directed against different hematopoietic lineage cells. Gaucher's cells and pseudo-Gaucher cells expressed a very similar immunophenotype and displayed an intense reaction for the monocytic antibodies tested, thus confirming their common origin and that they belong to the same system. The expression of HLA-DR antigens was much stronger in Gaucher's than in pseudo-Gaucher cells. This last finding, together with other serological data, suggests that Gaucher's cells could not behave simply as phagocytic cells but might play an active role in the chronic stimulation of the immune system that sometimes occurs in patients with Gaucher's disease.
A man dies because his body has rejected a heart transplant; a woman is crippled by rheumatoid arthritis; a child goes into a coma that is brought on by cerebral malaria; another child dies of an infection because of an immunodeficiency; an elderly man has advanced hepatic cirrhosis caused by iron overload. These five clinical situations are as diverse as can be, yet all have one thing in common: the cause of all of them involves the human leukocyte antigen (HLA) system, the human version of the major histocompatibility complex (MHC). Malfunction of the HLA system, which is at the . . .
Gaucher disease is a lysosomal storage disorder characterized by a deficiency of the enzyme acid beta-glucosidase. The clinical manifestations of Gaucher disease are highly variable, and although certain genotypes are often associated with mild or severe symptoms, a defined correlation between genotype and phenotype does not exist. Identification of biochemical markers characteristic of pathology may be of use in predicting the progression of the disease state. In this study the relationship among genotype, glycolipid substrates, lysosomal proteins, and the clinical manifestations of Gaucher disease has been evaluated. Plasma glycolipids were analyzed using electrospray ionization-tandem mass spectrometry. Lysosomal-associated membrane protein-1 (LAMP-1) and saposin C were determined by immunoquantification. Patients with Gaucher disease were shown to have an increased 16:0-glucosylceramide/16:0-lactosylceramide ratio and elevated concentrations of LAMP-1 and saposin C in plasma. A general relationship was found to exist among the 16:0-glucosylceramide/16:0-lactosylceramide ratio, LAMP-1 and saposin C levels, and patient phenotype, providing a refinement of the genotype-phenotype correlation. These findings have major implications for the diagnosis, prediction of disease severity, and monitoring of therapy in patients with Gaucher disease.
Gaucher disease, the most common lysosomal storage disorder, is caused by the defective activity of the lysosomal enzyme, acid-beta-glucosidase (GlcCerase), leading to accumulation of glucosylceramide (GlcCer), particularly in cells of the macrophage lineage. Nearly 200 mutations in GlcCerase have been described, but for the most part, genotype-phenotype correlations are weak, and little is known about the down-stream biochemical changes that occur upon GlcCer accumulation that result in cell and tissue dysfunction. In contrast, the clinical course of Gaucher disease has been well described, and at least one treatment is available, namely enzyme replacement therapy. One other treatment, substrate reduction therapy, has recently been marketed, and others are in early stages of development. This review, after discussing pathological mechanisms, evaluates the advantages and disadvantages of existing therapies.
Gaucher disease (GD) is an autosomal recessive inherited defect of the lysosomal enzyme glucocerebrosidase (GluCerase) that leads to glucosylceramide (GluCer) accumulation. We previously demonstrated the existence of imbalances in certain lymphocyte populations in GD patients. We now show that GluCerase-deficient monocytes from GD patients or monocytes from healthy subjects treated with conduritol-B-epoxide (CBE), an irreversible inhibitor of GluCerase activity, display high levels of surface expression of the lipid-binding molecule CD1d. GluCerase-deficient monocytes from GD patients also showed increased surface expression of major histocompatibility complex (MHC)-class II, but not of other lysosomal trafficking molecules, such as CD63 and MHC-class I. However, CD1d and MHC-class II mRNA levels were not increased. GluCerase-deficient monocytes from GD patients undergoing enzyme replacement therapy also exhibited increased levels of CD1d and MHC-class II and imbalances in the percentage of CD4+, CD8+, and Valpha24+ T cells. Interestingly, follow-up studies revealed that enzyme replacement therapy induced a decrease in MHC-class II expression and partial correction of the CD4+ T cell imbalances. These results reveal a new link between sphingolipid accumulation in monocytes and the expression of certain MHC molecules that may result in imbalances of regulatory T cell subsets. These immunological anomalies may contribute to the clinical heterogeneity in GD patients.
Using serologic human lymphocyte antigen (HLA) typing, the authors previously described a strong association between well differentiated thyroid carcinoma and HLA D-related 1 (HLA-DR1) in a population of unselected patients from Eastern Hungary.
In the current study, the authors used polymerase chain reaction-single strand conformational polymorphism to determine the HLA-DR type in 75 patients with well differentiated thyroid carcinoma from the same area as their previous population, and they compared the current results with the results from a group of 170 healthy controls.
A significant increase in HLA-DR11, rather than HLA-DR1, was observed in patients with well differentiated thyroid carcinoma among a population of patients from the same area that was studied previously. After excluding technical reasons to account for differences in disease association, they postulated that interim environmental factors, possibly radiation fall-out, may have resulted in differences in genetic susceptibility to thyroid carcinoma. Consideration of the potential antigenic peptides that may be restricted by the two HLA-DR alleles may have allowed for the binding of similar peptides to initiate an immune response, likely leading to progressive immunomodulation of the tumor. Discriminat function analysis indicated a significant relation between tumor size and metastases and less lymphocytic infiltration of the tumor, but this was not related to HLA-DR phenotypes.
The authors found that the study of major histocompatability complex alleles holds promise for understanding the events that initiate and maintain tumor immunomodulation.
Unlabelled:
Gaucher disease is the most common lysosomal storage disease. It is caused by a deficiency in the lysosomal enzyme glucocerebrosidase, a beta-glucosidase, which results in the accumulation of the lipid glucocerebroside in macrophages throughout the body. Gaucher disease is most common in the Ashkenazi Jewish population, and three mutations of the gene encoding glucocerebrosidase (GBA) have been shown to be prevalent in this population (c.1226 A > C [N370S], 84GG and IVS2[+1]). In non-Jewish patients, the most common mutation is c.1448 G > C (L444P). Until 15 years ago, treatment has been restricted to symptomatic interventions, such as splenectomy or hip replacement. However, there are now specific treatment options - enzyme replacement therapy and substrate reduction therapy. Future developments may include the use of chaperone therapy.
Conclusion:
The lessons that we have learned from Gaucher disease may well be applicable to the development of therapies for some of the other less common lysosomal storage diseases.
Type 1 Gaucher disease, the most common lysosomal storage disorder, results from deficiency of glucocerebrosidase causing pathologic accumulation of glucocerebroside. The disease is characterized by marked variation in age of onset and degree of anemia, thrombocytopenia, hepatosplenomegaly, and skeletal disease. Most published data on Gaucher disease come from populations with large proportions of Ashkenazi-Jewish patients, who tend to have less severe disease. We compared selected demographic, clinical, and genetic parameters for Brazilian (N = 221) and rest-of-world (N = 1477) type 1 Gaucher disease patients entered into the ICGG Gaucher Registry since 1991. We also compared Brazilian patients to non-Ashkenazi rest-of-world patients (N = 692) to determine if differences were the result of fewer Brazilian Ashkenazi-Jewish patients (0.5% vs 45.0%). The Brazilian cohort differed significantly (p < 0.05) from the rest-of-world and rest-of-world non-Ashkenazi cohort, respectively, in the following measures: higher proportion of females (59.7% vs 50.4% and 49.7%), lower mean age at diagnosis (17.1 vs 24.1 and 18.8), and higher proportions of patients with anemia (55.5% vs 29.9% and 35.7%), bone pain (57.7% vs 33.7% and 35%), bone crises (16.1% vs 6.5% and 7.4%), and lytic lesions (17.0% vs 7.6% and 7.4%). The most common genotype in Brazil was N370S/L444P (c1448T-->C/c1226A-->C) (46.8% versus 16.3% and 25.7%). These data highlight the genetic and phenotypic heterogeneity among geographic populations of type 1 Gaucher patients and suggest that as a group, Brazilian patients may have a more aggressive form of the disease than rest-of-world patients. The findings also emphasize the need for caution in making generalizations about Gaucher disease across demographic groups.
Gaucher disease is a lysosomal storage disorder, which is classically divided into three types. Type I Gaucher disease is differentiated from types II and III disease by the absence of nervous system involvement. However, an increasing number of reports has emerged on neurological manifestations in patients with type I Gaucher disease. Whether a strict division in three different phenotypes is still valid has been the subject of debate. The main objective of this study was to provide scientific arguments whether a distinction between type I (non-neuronopathic) and types II and III (neuronopathic) Gaucher disease should be maintained. We investigated retrospectively a large Dutch cohort of type I Gaucher disease patients for the prevalence of neurological manifestations and provide an overview of the literature on this topic. A diagnosis of a neurological disease was made 34 times in 75 patients. Forty-five patients reported at least one neurological symptom during the median follow-up time of 11 years. The literature search revealed 86 studies in which type I Gaucher disease patients or carriers of a glucocerebrosidase mutation were described with a neurological disease or a condition which is known to be associated with neurological disease. In conclusion, the term non-neuronopathic Gaucher disease does not seem to be an appropriate characterization of type I Gaucher disease. However, the neurological signs and symptoms in type I Gaucher disease are of a totally different kind from and, in the majority of cases, of much less severity than the signs and symptoms associated with types II and III disease Therefore, type I disease should be classified as a separate phenotype.
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