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Biomedical subjects

George Füst

Publications and source records attributed to George Füst.

At least 19 recordsLinked to original sources
PubMed2007

Relationship between copy number of genes (C4A, C4B) encoding the fourth component of complement and the clinical course of hereditary angioedema (HAE).

In order to study if in patients with hereditary angioedema (HAE), copy number of the two genes (C4A and C4A) encoded in the central region of main histocompatibility complex (MHC) influences the diagnostically important C4 serum concentration as well as the clinical course of the disease, we determined copy number of the complement C4A and C4B genes in DNA samples of 95 HAE patients and 246 healthy controls. Distribution of both the C4A and C4B copy numbers significantly (p=0.0183 and 0.0318, respectively) differed between the two groups, the most marked difference we observed was the lower frequency of the high (3 or 4) C4A copy numbers in the patients. As it expected, the dosage of both C4A and C4B genes positively correlated to the longitudinally measured serum C4 concentrations. Moreover, we found an unexpected clinical correlation with the dosage of the C4B gene. The course of the disease was milder in the 9/95 patients carrying 3 or 4 copies of C4B gene, compared to the rest of patients, i.e. diagnosis was established at significantly (p=0.0052) older age (36.0 (31.0-39.5)) years versus 20.5 (7.5-31.5 years), bi-yearly attack rate was significantly (p=0.0145) lower (1.0 (0.0-11.0)) versus 11.0 (3.5-21.5), and the over-all activity of the classical pathway and the enzyme-inhibitor activity of the C1-inhibitor (C1-INH) was closer to the normal values. These observations indicate that high copy number of the C4B gene can be a protective factor against disease severity in HAE and therefore its determination is warranted.

Adolescent↗
PubMed2006

Novel anti-cholesterol monoclonal immunoglobulin G antibodies as probes and potential modulators of membrane raft-dependent immune functions.

Natural autoantibodies against cholesterol are present in the sera of all healthy individuals; their function, production, and regulation, however, are still unclear. Here, we managed to produce two monoclonal anti-cholesterol antibodies (ACHAs) by immunizing mice with cholesterol-rich liposomes. The new ACHAs were specific to cholesterol and to some structurally closely related 3beta-hydroxyl sterols, and they reacted with human lipoproteins VLDL, LDL, and HDL. They bound, usually with low avidity, to live human or murine lymphocyte and monocyte-macrophage cell lines, which was enhanced substantially by a moderate papain digestion of the cell surface, removing some protruding extracellular protein domains. Cell-bound ACHAs strongly colocalized with markers of cholesterol-rich lipid rafts and caveolae at the cell surface and intracellularly with markers of the endoplasmic reticulum and Golgi complex. These data suggest that these IgG ACHAs may serve as probes of clustered cholesterol (e.g., different lipid rafts) in live cells and thus may also have immunomodulatory potential.

Antibodies, Monoclonal↗
PubMed2006

The 8.1 ancestral MHC haplotype is associated with delayed onset of colonization in cystic fibrosis.

Major cause of death in patients with cystic fibrosis (CF) is colonization with Staphylococcus aureus and Pseudomonas aeruginosa. The wide phenotypic variation in CF patients suggests that genes other than the cystic fibrosis transmembrane conductance regulator (CFTR) gene modify the disease. The 8.1 ancestral haplotype (8.1AH) in main histocompatibility complex is associated with alterations of the immune response. To study the influence of carriage of 8.1AH on frequency and onset of colonization in CF patients, DNA samples of 72 CF patients (39 homozygous and 33 heterozygous for DeltaF508) were genotyped for member alleles of the 8.1AH: HLA-DQB1*0201, HLA-DRB1*0301, receptor for advanced glycation end products (AGER) -429C, HSP70-2 -1267G (HSP70-2G) and tumor necrosis factor-alpha (TNF-alpha) -308A (TNF2). Colonization was verified by regular clinical and bacteriological screening. Frequency of colonization was significantly (P = 0.012) lower in the 8.1AH carriers; age, gender and DeltaF508 genotype-adjusted odds ratio to be colonized of the carriers versus non-carriers was 0.112 (0.024-0.520). According to survival analysis, patients with 8.1AH had significantly (P < 0.0001) longer colonization-free period compared with non-carriers. Our novel observations demonstrate that the 8.1AH is associated with delayed onset of colonization in CF, presumably by influencing defense mechanisms against infections.

Adolescent↗
PubMed2006

MBL and C1q compete for interaction with human endothelial cells.

C1q, the recognition molecule of the classical pathway of complement, binds to endothelial cells, leading to cell activation. Mannose-binding lectin (MBL), a recognition molecule of the lectin pathway, is structurally and functionally related to C1q. Therefore, we investigated the interaction of MBL with human umbilical vein endothelial cells (HUVEC). C1q and MBL were purified from normal human plasma and binding to HUVEC was evaluated by flow cytometry. Cross-competition experiments were performed using MBL and C1q labeled with digoxygenin. MBL, similar to C1q, exhibited a dose-dependent binding to HUVEC under calcium-free conditions, suggesting involvement of its collagenous domains. Pre-incubation of HUVEC with MBL inhibited the binding of digoxygenin-labeled MBL at equimolar concentrations, confirming the specificity of the interaction. Pre-incubation of HUVEC with MBL inhibited the binding of C1q and vice versa. Activation of HUVEC with LPS resulted in increased C1q and MBL binding. Stimulation of HUVEC with MBL did not result in a detectable increase in cytokine production. Based on these results, we propose that MBL and C1q bind to a shared receptor on endothelial cells. Interaction of MBL and C1q with receptors on endothelial cells may be involved in inflammatory processes, and in clearance of pathogens and apoptotic cells.

Apoptosis↗
PubMed2006

Modified low density lipoproteins differentially bind and activate the C1 complex of complement.

Several studies suggest that complement plays an important role in atherogenesis. To further investigate this question, we have studied the ability of native and modified forms of low density lipoprotein (LDL) to bind and activate C1, the complex that triggers the classical pathway of complement. For this purpose, LDL was both obtained commercially and purified according to an established procedure, and oxidized (oxLDL) and enzymatically modified (E-LDL) derivatives were generated from each preparation. Whereas the unmodified LDL and oxLDL samples did not activate C1 in the presence of excess C1 inhibitor, the E-LDL derivatives obtained by sequential treatment of LDL with a protease and then with cholesterol esterase triggered efficient C1 activation under these conditions, with activation levels approximately 60% upon incubation with 1 microM E-LDL for 90 min at 37 degrees C. In agreement with these findings, as shown by surface plasmon resonance spectroscopy (SPR), the C1q recognition subunit of C1 showed no interaction with unmodified LDL but bound to both E-LDL samples with high affinity (K(D)=58-75 nM). More unexpectedly, although they did not trigger direct C1 activation, both oxLDL samples were also efficiently recognized by C1q. Whereas the oxLDL derivative of commercial LDL activated C1 to a significant extent ( approximately 30%) in the presence of C-reactive protein (CRP), much lower activation levels (<10%) were obtained using the oxLDL derivative of purified LDL. As measured by SPR, CRP bound equally well to the oxLDL and E-LDL derivatives obtained from purified LDL. These data provide the first experimental evidence that E-LDL triggers efficient C1 activation under conditions close to the physiological situation, suggesting that activation of the classical complement pathway by this derivative may be a crucial factor in the pathogenesis of atherosclerosis. In contrast, it appears unlikely that oxLDL significantly activates C1 directly or in a CRP-dependent manner in vivo.

Animals↗
PubMed2006

C1-inhibitor (C1-INH) autoantibodies in hereditary angioedema. Strong correlation with the severity of disease in C1-INH concentrate naïve patients.

The presence of autoantibodies to C1-inhibitor (C1-INH-Abs) is a hallmark of acquired C1-inhibitor deficiency. However, only scarce data are available on their prevalence in hereditary angioedema (HAE). In a prospective study performed between 2001 and 2004 in 95 patients with Type I or II HAE, serum samples were taken one to three times a year and clinical status of the patients was registered. Serum samples were tested for total activity of the classical pathway, C1q, C3, C4 and C1-inhibitor (C1-INH) concentration and activity levels, as well as the presence of IgG, IgA and IgM type anti-C1-inhibitor antibodies (C1-INH-Ab). Fifty-four healthy age and gender matched persons served as control. Significant differences between the patients and controls in the occurrence of elevated (2S.D. higher than mean of control) C1-INH-Abs titers was found only in the case of IgM type C1-INH-Abs. Elevated (>4.22AU/ml) IgM C1-INH-Abs levels were found in 31 and 4% of the patients and controls, respectively (p<0.001). Surprisingly, high titer IgM C1-INH-Abs were present with equal frequency in the 41 HAE patients ever treated with C1-INH concentrate and in the 54 C1-INH treatment naïve patients. In the latter group, strong positive correlation between the levels of the IgM C1-INH-Abs and the most severe disease (score 1) (p=0.0021) and the yearly attack rate (p=0.0173) were obtained. In addition, the levels of the IgM C1-INH-Abs exhibited strong negative correlation to the C1-inhibitor concentration and functional activity, total classical complement pathway activity, and a positive correlation to total IgM concentration. Taken together, these data indicate that IgM type C1-INH-Abs are present with highly elevated frequency in HAE patients irrespectively of the previous treatment with C1-INH concentrate. Most probable production of these autoantibodies is the consequence of the activation of complement and other plasma enzyme systems during HAE attacks. Determination of IgM C1-INH-Abs can be used as an activity marker in HAE.

Adolescent↗
PubMed2006

Proinflammatory changes in human umbilical cord vein endothelial cells can be induced neither by native nor by modified CRP.

The role of C-reactive protein (CRP) in atherosclerosis is controversial. It is not clear, either, if the presumed endothelium-activating effect of CRP resides in native CRP (nCRP) or in a conformational isoform of CRP known as modified CRP (mCRP). In the present study we evaluated and compared the effect of nCRP, recombinant modified CRP (rmCRP) and urea-modified CRP (umCRP) on human umbilical vein endothelial cells (HUVECs). CRP preparations were carefully analyzed by biochemical, immunological and cell biological methods in order to avoid endotoxin or sodium azide contamination as well as inappropriate conformational changes, which together had possibly been the main reason for the previously published controversial results. Neither nCRP nor mCRP showed significant cytotoxicity up to 100 microg ml(-1) at 24 h but high concentrations of CRPs induced cell death at 48 h. rmCRP but not nCRP nor umCRP showed membrane binding to HUVEC by confocal microscopy. However, none of the CRP forms induced intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin expression or IL-8 production. Monocyte chemotactic protein-1 production was weakly inhibited by high concentration of both nCRP and rmCRP, analyzed by sandwich ELISA. Neither nCRP nor mCRP could induce pro-inflammatory changes in the phenotype of HUVECs. Therefore, our present findings do not support the notion that different isoforms of CRP alone have significant effects on inflammation of the vessel wall via an interaction with endothelial cells (ECs), although one cannot exclude the possibility that there may be significant differences among various types of ECs in the response to CRP.

Atherosclerosis↗
PubMed2006

The HLA 8.1 ancestral haplotype is strongly linked to the C allele of -429T>C promoter polymorphism of receptor of the advanced glycation endproduct (RAGE) gene. Haplotype-independent association of the -429C allele with high hemoglobinA1C levels in diabetic patients.

Previously we reported on strong linkage disequilibrium (LD) between the mono-S-C4B-RCCX module (mono-S) and the TNF2 allele (both known constituents of the 8.1 ancestral haplotype (8.1 AH)) in two Caucasian populations. The gene for the receptor of advanced glycation endproducts (RAGE) is encoded between the RCCX module and the HLA class II genes in the central MHC region. In order to assess the relationship between the promoter polymorphisms of the RAGE gene and the 8.1 AH, we performed a family study in eight informative families affected with type 1 diabetes mellitus; haplotypes of a RAGE promoter SNP (-429T>C) with the HLA-DQ2, -DR-3(17) and TNF2 alleles, as well as the mono-S genotype were determined. A similar analysis was performed in 82 unrelated patients with type 1 diabetes mellitus, and in unrelated healthy individuals of three different Caucasian populations (Hungarians, Ohioian females, Icelandics). In the diabetic patients clinical correlations were also investigated. Out of the 32 paternal and maternal chromosome 6 from the eight families, 15 different MHC haplotypes were found. Haplotypes containing at least three of the known constituents of the 8.1 AH (HLA-DQ2, -DR17, mono-S, TNF2) were always linked to the RAGE -429C allele. The RAGE -429C allele exhibited highly significant (p<0.0001) LD coefficients to known constituents of the 8.1 AH both in healthy persons and patients with type 1 diabetes. In the group of patients with diabetes we found significantly (p=0.013) higher maximal hemoglobinA1C concentration in the carriers of the RAGE -429C allele, this trait, however was not linked to the 8.1 AH. Our present findings indicate that the RAGE -429C allele can be considered as a candidate member of the 8.1 AH. The results also reveal a spectrum of recombinant MHC haplotypes in addition to the conserved ancestral haplotypes.

Adolescent↗
PubMed2006

Decreased frequency of the TNF2 allele of TNF-alpha -308 promoter polymorphism is associated with lacunar infarction.

BACKGROUND AND PURPOSE: Enhanced release of proinflammatory cytokines may contribute to the pathogenesis of stroke. It was examined whether G to A promoter polymorphism in the tumor necrosis factor-alpha gene at position -308 affects the risk of stroke. METHODS: We genotyped 336 patients with ischemic stroke and 333 healthy controls for this polymorphism. Patients were divided into different groups based on the Oxfordshire Community Stroke Project (OCSP) or a modified TOAST classification. Distribution of the alleles at -308 G>A promoter polymorphism was determined by PCR-RLFP method. RESULTS: Patients with ischemic stroke had a significantly (p<0.001) decreased (0.115) frequency of the -308 A (TNF2) allele compared to the healthy controls (0.196). When patients were categorized according to the OCSP classification, it turned out that significant (p=0.002) decrease in TNF2 allele frequency (0.065) was restricted to the patients with lacunar infarct (LACI) whereas the frequency of the TNF2 alleles in patients with the other three subtypes (TACI, PACI, and POCI) did not significantly differ from that in healthy controls. Similar results were obtained when the patients were divided according to the modified TOAST classification: the frequencies of the TNF2 allele were 0.068 and 0.140 (p=0.010) in the patients with small-vessel and non-small vessel (large vessel infarction or ischemic stroke of other origin) infarction, respectively. The age-adjusted odds ratio of the patients carrying the TNF2 allele to develop lacunar infarct was 0.33 (0.16-0.68) (p=0.002) compared to the non-carriers. This difference was also restricted to the male patients. CONCLUSIONS: Our results suggest that male carriers of TNF2 allele are less susceptible for the development of lacunar subtype of ischemic stroke than the non-carriers.

Aged↗
PubMed2006

Determination of complement factor H functional polymorphisms (V62I, Y402H, and E936D) using sequence-specific primer PCR and restriction fragment length polymorphisms.

BACKGROUND: Complement factor H (CFH; HF) is an essential regulatory protein that plays a critical role in the homeostasis of the complement system in plasma. Several polymorphisms and mutations in the complement factor H gene (CFH; HF1) have been identified. These have revealed interesting associations with hemolytic-uremic syndrome and age-related macular degeneration. METHODS AND RESULTS: The aim of this study was to develop a rapid and reliable assay for determining genotypic variants of the CFH gene. Sequence-specific primer PCR and restriction fragment length polymorphism techniques were chosen for the analysis of CFH polymorphisms. The assays detected the following published single nucleotide polymorphisms of CFH in our Caucasian population (n = 271): rs800292, 257G-->A (V62I); rs1061170, 1277T-->C (Y402H); and rs1065489, 2881G-->T (E936D). The allele frequencies (257G = 0.850, 1277T = 0.574, and 2881G = 0.839) that we obtained from a healthy Hungarian population were consistent with previously published results. CONCLUSION: These analytical methods are simple, reliable, and rapid to perform, and are amenable to automation. Therefore, they could facilitate large-scale genotypic analyses of the CFH gene in various diseases, such as hemolytic-uremic syndrome, age-related macular degeneration, and cardiovascular diseases.

Adult↗
PubMed2006

Elevated complement C3 is associated with early restenosis after eversion carotid endarterectomy.

Early restenosis following carotid endarterectomy (CEA) is an inflammatory process leading to myointimal hyperplasia of smooth muscle cells. The risk for restenosis is increased in homozygous carriers of the normal (A) allele of mannose-binding lectin (MBL2) gene. Our objective was to study the associations of C3 and as control three non-complement acute-phase reactants (APRs) (C-reactive protein, haptoglobin and alpha2HSglycoprotein) with early restenosis following CEA. We also considered, whether MBL2 genotype relates to C3 levels and to the risk of restenosis. Concentrations of the APRs were determined by radial immunodiffusion or immunoturbidimetric methods in 64 patients who underwent eversion CEA and were followed up with carotid duplex scan (CDS) examinations for at least one year. MBL2 genotypes were determined by a PCR-SSP method. C3 levels increased during the follow-up and correlated with the percentage of restenosis detected by CDS at 14 months postsurgery, in MBL2 A/A allele carriers. Patients with high C3 levels had nearly five-fold higher odds for the presence of significant restenosis (>50% reduction in diameter) even after adjusting for MBL2 genotype, age and gender. By contrast, no such associations were detected between the non-complement APRs and early restenosis. C3 is associated with and might have a direct role in the development of an early restenosis following CEA, which is partially related to an intact MBL lectin pathway, thus determining C3 levels might have clinical importance. On the other hand, our results indicate that the regulation of C3 differs from non-complement APRs.

Adult↗
PubMed2005

High rate of early restenosis after carotid eversion endarterectomy in homozygous carriers of the normal mannose-binding lectin genotype.

BACKGROUND AND PURPOSE: Mannose-binding lectin (MBL) is thought to influence the pathophysiology of cardiovascular disease by decreasing the risk of advanced atherosclerosis and by contributing to enhanced ischemia reperfusion injury. Thus, we investigated the role of MBL in restenosis after eversion endarterectomy in patients with severe carotid atherosclerosis. METHODS: In a prospective study, 123 patients who underwent carotid endarterectomy were followed-up by carotid duplex scan (CDS) sonography for 14 months. In a retrospective study, we examined 17 patients and 29 patients, respectively, who had or had not at least 50% restenosis 29 months after carotid eversion endarterectomy. MBL genotypes were analyzed by a polymerase chain reaction-based method, and MBL serum concentrations were measured. RESULTS: In the prospective study in the patients homozygous for the normal MBL genotype, CDS values were significantly higher after 14 months of follow-up compared with the values measured 6 weeks after surgery (P<0.001). In contrast, only a slight increase was registered in patients carrying MBL variant alleles. The differences were much more pronounced in female than in male patients. Similar differences were observed when patients with high and low MBL serum concentrations were compared. In the retrospective study, a significant increase in the frequency of MBL variant genotypes was observed in patients not experiencing restenosis compared with the patients with restenosis (P=0.007). CONCLUSIONS: These results indicate that reoccurrence of stenosis after carotid endarterectomy is partially genetically determined and imply that MBL contributes significantly to the pathophysiology of this condition.

Aged↗
PubMed2005

Dramatic changes in the serum levels of anti-cholesterol antibodies after eversion endarterectomy in patients with severe carotid atherosclerosis.

Our goal was to study changes in anti-cholesterol antibodies (ACHA) levels in patients with severe carotid stenosis after eversion endarterectomy. Seventy consecutive patients who underwent eversion endarterectomy at the Department of Cardiovascular Surgery, Semmelweis University, Budapest, were included in the study. Serum samples from 66 healthy volunteers served as controls. Patients had medical check up at 5.7 (4.6-8.0) weeks (median (interquartile range)), 6.8 (6.2-7.9) months as well as 13.8 (12.3-19.0) months after endarterectomy. In all patients the carotid arteries were investigated by color duplex ultrasound. ACHA concentrations were determined in the serum samples taken before operation as well as at the first and last follow-up visits by using an ELISA method. ACHA concentrations (median (interquartile range) were found to be significantly (p<0.0001) lower in the sera of the patients with carotid atherosclerosis (13.5 (8.4-21.3)AU/ml) than in the healthy subjects (26.1 (20.9-33.2)AU/ml) (Mann-Whitney test). Strong negative correlation was found between the preoperative ACHA and LDL-cholesterol levels (r=-0.413, p=0.0004). Serum ACHA concentrations significantly (p<0.0001) increased from the values measured before operation (13.5 (8.4-21.3)AU/ml) to 27.1 (19.9-34.7)AU/ml measured at the end of the 14 months long follow-up. Increase occurred only in patients with low or medium baseline ACHA concentration. Our present findings indicate that after surgical removal of atherosclerotic plaques from the carotid arteries the reduced baseline levels of ACHA reach normal values in 1 year. Different not mutually exclusive mechanisms (binding of ACHA to lipid/lipoproteins particles, to advanced plaques or reversibly injured endothelial cells in CNS) can be responsible for this novel finding.

Acute-Phase Proteins↗
PubMed2005

Development of a sensitive assay for the measurement of antibodies against heat shock protein binding protein 1 (HspBP1): increased levels of anti-HspBP1 IgG are prevalent in HIV infected subjects.

The 70 kDa heat shock protein (Hsp70) is generally considered to be an intracellular protein, however, there is evidence that Hsp70 can be found in the extracellular environment. Hsp70 and antibodies against Hsp70 have been reported in human serum. Recent evidence has shown that Hsp70 antibodies are elevated in HIV infected individuals. This study reports on the antibody levels against a co-chaperone, HspBP1, that regulates Hsp70 activity. We have developed a solid-phase enzyme linked assay for the determination of anti-HspBP1 IgG antibodies. We report here that HspBP1 antibodies are present in human serum and the levels are elevated approximately twofold in HIV infected patients. There was no correlation between HspBP1 antibody levels and clinical parameters nor was there a relation between anti-Hsp70 levels and anti-HspBP1 levels. The presence of HspBP1 antibodies in human serum suggests that the protein may also be present in the serum. The increased level of HspBP1 antibodies in HIV infected individuals suggests a relationship directly to the virus or indirectly to secondary consequences of HIV infection.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Adverse effects of danazol prophylaxis on the lipid profiles of patients with hereditary angioedema.

BACKGROUND: Hereditary angioedema (HAE) is a rare disorder caused by the deficiency of the C1-inhibitor gene (C1INH) . Patients experience recurrent bouts of edema, which can occur in almost any region of the body. As regards the treatment of the disease, danazol (an attenuated androgen) is used, among other agents, for long-term prophylaxis. OBJECTIVE: The aim of this study was to investigate the possible adverse effects of danazol on serum lipid profile, as well as to ascertain whether danazol treatment is associated with an increased risk of atherosclerosis. METHODS: Serum concentrations of total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides, apolipoprotein A-I, apolipoprotein B-100, and lipoprotein(a) were compared between danazol-treated patients with HAE and 2 control groups (ie, patients who did not receive long-term danazol prophylaxis and untreated healthy subjects). RESULTS: Serum concentrations of HDL ( P = .0002 and P < .0001) and apolipoprotein A-I ( P = .0015 and P < .0001) were significantly lower, whereas LDL ( P = .0129 and P = .0127) and apolipoprotein B-100 ( P = .0456 and P = .0013) were higher in the danazol-treated patients compared with the 2 control groups, respectively. No significant difference was found in total cholesterol, triglyceride, or lipoprotein(a) levels. Patients who received danazol had an 11.6 (95% CI, 2.7-49.7) times higher risk for abnormally low HDL levels and a 4.4 (95% CI, 1.2-16.0) times lower risk for high LDL concentrations. CONCLUSIONS: Our findings indicate that the long-term use of danazol is associated with an increased risk for early atherosclerosis in patients with HAE. Consequently, monitoring of HDL and LDL levels at regular intervals is recommended during follow-up.

Adult↗
PubMed2005

Antibodies against heat shock proteins and cholesterol in HIV infection.

This review summarizes data on the presence and function of different heat shock proteins (Hsp) in the HIV virions and the infected cells. A 60 kD heat shock protein-like molecule is present in the envelope of the human immunodeficiency virus type 1 which can specifically interact with the transmembrane glycoprotein gp41. The role of cholesterol in the so-called cholesterol-rich lipid raft where HIV is budding from the infected cells as well as the consequential insertion of cholesterol into the envelope of HIV virion are also discussed. Natural antibodies against 60 kD (Hsp60) and 70 kD (Hsp70) families of Hsp and cholesterol can be detected in most healthy individuals. HIV infection results in a sharp increase in the serum concentration of anti-Hsp70 and cholesterol antibodies whereas no difference in the concentration of anti-Hsp60 antibodies can be detected. Highly active antiretroviral therapy leads to normalization of the levels of both anti-Hsp70 and anti-cholesterol antibodies.

Autoantibodies↗
PubMed2005

Association between interleukin-6 polymorphism and age-at-onset of type 1 diabetes. Epistatic influences of the tumor necrosis factor-alpha and interleukin-1beta polymorphisms.

Multiple immune mediators have been mentioned as playing a role in the pathomechanism of type1 DM. Interleukin (IL)-1beta, and tumor necrosis factor (TNF)-alpha play a central role in the autoimmune destruction of pancreatic beta-cells, whereas IL-6 inhibits TNF-alpha secretion, and may have some protecting effects. In our study, we aimed to investigate the association between these three cytokines' single nucleotide polymorphisms (IL-6 gene G(-174)C, TNF-alpha gene G(-308)A and IL-1beta gene C(3954)T polymorphisms) and age-at-onset of type 1 diabetes mellitus (T1DM) in 165 diabetic children (median age: 17 years). Polymorphisms were determined using the PCR-RFLP method. We found that the age-at-onset of T1DM was significantly different in patients with a different IL-6 genotype (median age-at-onset of T1DM was: 8, 6 and 4.5 years in children with the (-174)GG, GC and CC genotypes, respectively; p < 0.01). Adjusted for TNF-alpha and IL-1beta polymorphisms, patients with a IL-6 (-174)CC genotype have a 3.0-fold (95% CI: 1.2-7.1) increased risk of developing diabetes before the age of 6 years than (-174)G allele carrier patients. However, we found this association to be present only in patients who carried the TNF-alpha (-308)A or IL-1beta (3954)T allele, i.e. in patients with high TNF-alpha and high IL-1beta producer genotypes. We suppose that in the case of high TNF-alpha and IL-1beta producer genotypes, elevated proinflammatory cytokine levels result in a higher production of IL-6 in (-174)G allele carrier patients. This elevated IL-6 level may have a protective effect against the development of T1DM and may delay the destruction of pancreatic beta-cells.

Age of Onset↗