Natural evolution of hepatitis C virus infection in hemodialysis Tunisian patients and CTLA-4 SNP's.

AIM: To analyze the polymorphisms of CTLA-4 gene involved in the response against hepatitis C virus (HCV) infection. METHODS: We recruited 500 hemodialysed patients from several hemodialysis centers, all HCV-antibody positive, spread over different regions of Tunisia, as part of a national survey in 2008 conducted in the laboratory of immunology at the Charles Nicolle hospital Tunisia, classified into two groups G1 (PCR+) and G2 (PCR-) according to the presence or absence of viral RNA. Of these patients, 307 were followed prospectively on a viral molecular level over a period from 2002 to 2008, divided into two groups based on the persistence and viral clearance. PCR-RFLP was performed for the analysis of SNPs (+49) A/G and (+6230) G/A CTLA-4 for these 500 patients and 358 healthy controls. RESULTS: Analysis of clinical and virological characteristics of our cohort suggests a nosocomial infection in our hemodialysed patients with transfusion history as a primary risk factor and a predominance of genotype 1b. The haplotype analysis revealed an increase of frequencies of GG (+49)/(CT60) CTLA-4 in the entire patients group compared to controls (P = 0.0036 and OR = 1.42; 95%CI: 1.12-1.79, respectively). This haplotype is therefore associated with susceptibility to HCV infection. CONCLUSION: Our study suggests a possible role of CTLA-4 polymorphisms in the outcome of HCV infection in the Tunisian hemodialysed population.

Phylogenetic analysis of isolated HCV strains from tunisian hemodialysis patients.

The present study describes the strains of hepatitis C virus (HCV) isolated from Tunisian hemodialysis patients. Thirty-three HCV strains isolated from different dialysis centers in Tunis City were amplified by RT-PCR in a region of the NS5b gene, genotyped by sequencing, and compared to international sequences by phylogenetic analysis. The phylogenetic tree showed that 16 HCV isolates have been identified as subtype 4k (48.5%), 7 as unspecified HCV-4 subtype (21.2%), 5 as subtype 4a et 1b (each 15.2%). The analysis of this tree revealed that the HCV-1b strains were closely related to Anglo-Saxon and European isolates, while the HCV-4 isolates are genetically similar to Egyptian and African strains. Phylogenic analysis of 33 Tunisian isolates with international HCV strains on a region of the NS5b gene demonstrated that the subtype 4k submerged the Tunis city and a new subtype of HCV4 seems to be suspect in this area.

Investigation of DNA sequence in the Basal core promoter, precore, and core regions of hepatitis B virus from Tunisia shows a shift in genotype prevalence.

BACKGROUND: In this study, we evaluated the prevalence of the most common mutations occurring in Enhancer II (EnhII), Basal Core Promoter (BCP), Precore (PC), and Core (C) regions of hepatitis B virus (HBV) genome. OBJECTIVES: We also investigated the correlation between HBV variants, their genotypes, and patients' HBe antigen (HBeAg: soluble shape of the capsid antigen) status. PATIENTS AND METHODS: We retrieved viral DNA from 40 serum samples of Tunisian patients positive for hepatitis B surface antigen (HBsAg) and HBV DNA, amplified the above mentioned regions using specific primers, and sequenced the corresponding PCR (polymerase chain reaction) products. For further analysis purpose, the patients were divided into two groups: Group1 including 34 HBeAg-negative patients and Group2 with 6 HBeAg-positive patients. RESULTS: Twenty-one patients (52.5%) showed PC G1896A mutation and 11 (27.5%) carried A1762T/G1764A double mutations. These mutations were more frequent in HBeAg-negative patients than that in HBeAg-positive ones. Indeed, 58.8% of patients bearing G1896A mutation were HBeAg-negative while 16.7% were positive. In patients bearing T1762/A1764 double mutation, 29.4% were positive and 16.7% were negative. In addition, the A1896 mutation was restricted to HBV isolates that had wild-type T1858, while C1858 was rather linked to the occurrence of T1762/A1764 mutation. Interestingly, this study revealed a high frequency of genotype E. This frequency was important as compared to that of genotype D known to be predominant in the country as delineated in previous studies. CONCLUSIONS: Previous results supported and showed that HBV strains present in Tunisia belonging to genotype D and, to a lesser extent, to genotype E, were prone to mutations in BCP/ PC regions. This observation was more obvious in HBV isolates from asymptomatic chronic carriers (AsC). The high mutational rates observed in our study might result from a mechanism of viral escape that plays an important role in the loss of HBeAg.

Chemokine and chemokine receptor gene polymorphism in Tunisian hemodialysis patients with HCV infection.

INTRODUCTION: Our aim was to investigate the possibility of a significant relationship between chemokines and chemokine receptor genes polymorphisms and the spontaneous clearance or the persistence of HCV infection. METHODS: A total of 96 hemodialysis (HD) patients infected with HCV were classified into two groups: G1 included 73 patients with persistently positive HCV-RNA and G2 included 23 HD patients who have spontaneously eliminated the virus. The control group consisted of 170 healthy blood donors. All subjects were genotyped for CCR5 ?32, CCR5 (-59029) A/G, CCR2 (64Ile) and MCP-1(-2518) A/G gene polymorphisms. RESULTS: Our results showed a statistically significant increased frequencies of the CCR2 (64Ile) and the (-59029) CCR5 A alleles in patients infected with HCV (22.1% and 35.9%) compared to G1 (24.3% and 40.6%) and compared to controls (14.4% and 20%). We also observed a lower frequency of the MCP-1 G allele and a greater frequency of the CCR5?32 variant in G2 (15.2% and 6.5%) compared to G1 (22.6% and 1.4%) that was not statistically significant. However, adjustment for known covariates (age, gender and HCV genotypes) didn't confirm the results of univariate analysis. CONCLUSION: In conclusion, our study suggests a possible role for some of the studied chemokines polymorphisms in the spontaneous clearance or persistence of HCV infection in Tunisian population. These results should be further investigated by a prospective cohort studies and large population-based studies.

Cytokine and apoptosis gene polymorphisms influence the outcome of hepatitis C virus infection.

BACKGROUND: Hepatitis C virus (HCV) infection is thought to be chronic and the factors leading to viral clearance or persistence are poorly understood. This study was undertaken to investigate the possibility of a significant relationship between the spontaneous clearance or the persistence of hepatitis C virus (HCV) infection and cytokine and apoptosis gene polymorphisms in Tunisian patients on hemodialysis. METHODS: Polymorphisms of the genes IL-1 (-889 IL-1alpha, -511 and +3954 IL-1beta, IL-1Ra), IL-18 (-137 and -607), IL-12 (-1188) and Apo1/Fas (-670) were determined by PCR-RFLP, PCR-SSP and PCR-VNTR in 100 healthy blood donors and 100 patients infected with HCV and undergoing hemodialysis. The patients were classified into two groups: G1 consisted of 76 active chronic hepatitis patients (positive for HCV RNA) and G2 consisted of 24 hemodialysed patients who spontaneously eliminated the virus (negative for HCV RNA). RESULTS: The frequency of genotype association [-137GC/-607CA] IL-18 was higher in G2 (41.7%) than in G1 (15.8%) (P=0.008; OR=0.26; 95% CI, 0.10-0.73). We also found a higher frequency of the AA genotype of the Apo1/Fas gene in G2 (41.6%) than in G1 (17.5%) (P=0.026; OR=3.49; 95% CI, 1.13-10.69). Adjustment for known covariate factors (age, gender and genotype) confirmed these univariate findings and revealed that the genotype association GC-CA of the (-137 and -607) IL-18 gene and the AA genotype of the Apo1/Fas gene were associated with the clearance of HCV (P=0.041 and 0.017, respectively). CONCLUSION: The two genotypes GC-CA of the (-137 and -607) IL-18 polymorphism and the AA genotype of the Apo1/Fas gene influence the outcome of HCV infection in Tunisian patients on hemodialysis.

CD86 +1057G>A polymorphism and susceptibility to acute kidney allograft rejection.

INTRODUCTION: CD86 is a costimulatory molecule that participates in the regulation of T-cell lymphocytes activation. Thus, we examined a genetic marker on the CD86 gene in kidney transplant outcome. MATERIALS AND METHODS: In our retrospective study, 168 kidney allograft recipients were genotyped by direct sequencing. Patients were classified into 2 groups of 29 human leukocyte antigen (HLA)-identical haplotype allograft recipients and 139 recipients showing one or more mismatches in the HLA haplotype. Forty-five patients (26.8%) developed at least 1 acute rejection (AR) episode, 7 in the first and 38 in the second group. RESULTS: Acute rejection was associated with the presence anti-HLA antibodies before transplantation (P = .03). The AA genotype and A allele at position +1057 in the CD86 gene were more frequent in patients without AR (9.75% and 28.5%, respectively) compared with those showing an AR (2.22% and 23.3%, respectively). This difference was statistically significant in the anti-HLA-positive recipients, as AA frequency was 31.3% in non-AR patients and zero in AR ones (P = .04) and A allele frequency was 46.9% and 20.8%, respectively (P = .04). Patients bearing AA genotype reached a higher graft survival time (9.84 years) than those carrying GA (8.21 years, P = .32) or GG (7.61 years, P = .72) genotypes. CONCLUSIONS: These results suggest that AA genotype and A allele of CD86 +1057G>A polymorphism may confer a protection against acute kidney allograft rejection in Tunisian patients.

Interleukin-18 gene polymorphisms in tunisian patients with inflammatory bowel disease.

AIM: Interleukin (IL)-18 can regulate the Th2-mediated immune response and it may be involved in the pathogenesis of Th1 and Th2 chronic inflammatory diseases. This study sought to detect a possible association between two single nucleotide polymorphisms (SNPs) (-137G/C and -607C/A) in the IL-18 gene promoter region and susceptibility to inflammatory bowel disease (IBD) including Crohn's disease (CD) and ulcerative colitis (UC) in the Tunisian population. METHODS: The (-137G/C and -607C/A) IL-18 polymorphism was analyzed in 105 patients with CD, 59 patients with UC, and 100 controls using the sequence-specific polymerase chain reaction method. RESULTS: The distribution of allele and genotype frequencies illustrate that the -137G/G genotype frequency was significantly higher in UC than in controls (p value corrected (pc) = 0.038). On the other hand, we found a statistically significant association (pc = 0.033) between genotype AA of the IL-18 gene promoter (-607C/A) polymorphism in UC patients and the distal localization of the lesions. In CD, no significant differences were observed at positions -607 and -137. The analysis of IBD patients according to clinical behavior revealed no difference. CONCLUSION: The two SNPs at position -607 (C/A) and -137 (G/C) in the promoter region of the IL-18 gene was associated with the development of UC but not CD, providing a strong support for an IBD susceptibility gene in the region surrounding IL-18. It remains to be determined precisely how the IL-18 alleles influence the pathogenesis of IBD.

[Hepatitis C in kidney transplantation: comparative study between two Maghrebin centers: Casablanca and Tunis]. / L'hépatite virale C au cours de la transplantation rénale: étude comparative entre deux centres Maghrébins: Casablanca et Tunis.

BACKGROUND: Hepatitis viral C (HVC) is relatively frequent among kidney transplants. It is responsible for a morbid-mortality that compromises the results of transplantation in the medium and long term. AIM: To evaluate and to compare the prevalence of HVC, 172 kidney transplant adult patients were investigated in two Maghrebian centers at Casablanca (G1): 57 Moroccan patients and Tunisia (G2):.115 Tunisian patients. The impact of the HVC infection for a morbid-mortality was concerned only the Tunisian recipient patients: 20 kidney recipients having antibodies anti-VHC and positive HVC-RNA (Cases) which were matched in age, sex and date of the kidney graft, to 20 kidney transplant patients anti-HVC and VHCRNA negative (Controls). METHODS: The anti-VHC antibodies were detected by ELISA: Innogenetics and their positivity were confirmed by RIBAII. The ARN-VHC was analyzed by RT-PCR INNO-LiPA HCV II amplification of Innogenetics. RESULTS: The prevalence of hepatitis C is similar for the two groups: 19.3% among Moroccan kidney transplants and 20.9% among Tunisians. The infection by the HVC was often active and the detection of viral RNA was found in 91.7% of the G2 patients against 50% among G1 patients. The genotype 1b is the most prevalent; it is found in 59% of the patients. The frequency of HVC among our kidney transplant patients is particularly determined by the duration and the mode of dialysis. In fact, 22.1% of the patients treated by hemodialysis are VHC (+) against 5,6% patients treated by peritoneal dialysis. Also, the average duration of the dialysis is 58,8 months for HVC (+) patients against 33.5 months for HVC (-) (p<0.0001) patients. The frequency of the chronic rejection of the graft is higher in the G2, but it is similar in Tunisian patients with or without antibodies anti-HVC. In the G1, this frequency is statistically higher among positive HVC transplant patients compared to the negative HVC grafted patients (p<0.05). The case-control study emphasizes the frequency of the proteinuria, the renal insufficiency, the mellitensis diabetes and the polyglobulinemia among patients HCV (+); however the differences between the two groups remain statistically non significant. The total rate of the hospitalizations is 26 per 100 patients per year in the HCV (+) group against 17 for the HCV (-). The average duration of hospitalizations is 72 days among HCV (+) patients against 30.2 days for the controls (p<0.05). The averages of survival of the patients and of the controls were similar 11.6±5.6 years for transplant patient HCV (+) against 11.2±5.5 years for the controls. The actuarial curves of the patients were not different for the patients having antibodies anti-HCV positive or negative. CONCLUSION: The blood and nosocomial modes of contamination of HVC infection explain their higher frequency in this population at risk. The mortality and the morbidity of the renal transplant patients infected by the HCV seem to be higher compared to the uninfected patients. A further study by large population should be carried out to confirm these results.

[IL1/IL1 Ra, CTLA-4 and Apo1/Fas genes polymorphisms and susceptibility to IgA nephropathy in Tunisian patients]. / Polymorphismes des gènes de l'IL1/IL1 Ra, CTLA-4 et Apo1/Fas et susceptibilité à la néphropathie à IgA chez des patients Tunisiens.

BACKGROUND: The IgA nephropathy (IgA-N) is considered the most common form of primary glomerulonephritis and its pathogenic mechanisms are very complex. The study of several genes which encode for immunoregulator molecules in inflammatory and immunological responses during the disease, allowed to describe some number of polymorphisms would be involved in the molecular expression, the road marking, the synthesis and\or the binding to the receptors. So an abnormality of the molecular function associated with its polymorphism would be suggested in the genetic predisposition to the disease. AIM: To determine interleukin 1 (IL1), interleukin1 receptor antagonist (IL1 Ra), CTLA-4 and Apo1/Fas genes polymorphisms frequencies in IgA-N in order to estimate the impact of these polymorphisms in the disease susceptibility. METHODS: The polymorphism of a single nucleotide (SNP) at (-889) IL1 a of 21 IgA-N patients and 100 healthy blood donors, as controls, was studied by PCRSSP. The SNPs of the IL1 ß (+3954), CTLA-4 (+49) and l'Apo1/Fas were analyzed by PCR RFLP and finally the polymorphism of the IL1 Ra gene was determined by a PCR VNTR (variable number tandem repeat). RESULTS: Investigation of IL1a/ß and Apo1/Fas polymorphisms showed no differences in genotypes and alleles frequencies between IgA-N patients and controls. However, genotype AA of CTLA-4 exon1 (+49) was significantly higher in patients (47.62%) than in controls (9.1%) p<0.001. Nevertheless, the clinical, histological and biological characteristics of IgA-N were similar in AA CTLA-4 genotype patients compared to AG or GG genotype patients. We fund also, a significant increased frequency of 1/1 IL1 Ra genotype in IgA-N patients (95.24%) compared to controls (54%) (p<0.001) (p<0.001). CONCLUSION: We conclude that the susceptibility to IgA-N seems to be associated with the presence of CTLA-4 AA and IL1 Ra 1/1 genotypes in Tunisian population. However, the lack of association between IL1 a/ß and Apo1/fas genes polymorphisms should be further investigated by large population based studies.

Lymphoid tyrosine phosphatase R620W variant and inflammatory bowel disease in Tunisia.

AIM: To assess the possible association between PTPN22 (R620W) gene polymorphism and inflammatory bowel disease (IBD). METHODS: One hundred and sixty-four patients with IBD [105 Crohn's disease (CD) and 59 ulcerative colitis (UC)] and 100 healthy controls were recruited. Genotyping of the PTPN22 gene 1858C-->T polymorphism was performed by restriction fragment length polymorphism-polymerase chain reaction with RsaI digestion. RESULTS: The genotypic and allelic frequencies of (R620W) PTPN22 gene polymorphism reveal a significant association of the PTPN22 620-W allele with IBD, compared to the healthy control group (OR: 17.81, 95% CI: 4.18-21.86, P = 0.00001). Nevertheless, no difference in this polymorphism was found between CD and UC patients. No significant association was found between the frequencies of genotypes of the PTPN22 gene with either the clinical features such as sex, age, age at disease onset, and extent of colitis, or the production of serological markers (anti-Saccharomyces cerevisiae antibody in CD and perinuclear anti-neutrophil cytoplasmic antibody in UC). CONCLUSION: These observations confirm the association of IBD susceptibility with the PTPN22 1858T (620-W) allele in Tunisian patients.

Role of genetic polymorphisms in factor H and MBL genes in Tunisian patients with immunoglobulin A nephropathy.

The molecular mechanisms of IgA nephropathy (IgAN) remain poorly understood. Several different polymorphic genes have been investigated in order to demonstrate their possible association with this disease. It is evident that mainly alternative and lectin pathways complement activation and play an important role in renal injury of IgAN. This study was conducted to determine eventual deficiencies of factor H in the SCR20 gene region and to look for a possible association between the polymorphism (+54) exon 1 of the MBL gene and the predisposition in Tunisian patients with IgAN. We then evaluated the effects of these FH mutations and/or this MBL polymorphism on nephropathy susceptibility and progression. Polymorphism A/B (+54) in the exon1 of the MBL gene and analysis within the C-terminal domain of the protein SCR20 in the exon 22 of the factor H (FH) gene were conducted in 36 sporadic IgAN Tunisian patients and 117 age and gender matched healthy subjects recruited from blood donors, by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and direct sequencing respectively. The analysis of the Gly54Asp (+54) mutation of the MBL gene according to the criteria of gravity of the IgAN reveals that the patients with genotype AB present more frequently with end-stage renal disease (ESRD) compared with those of genotype AA [OR: 8, CI (1.74-54.49), P = 0.019]. Moreover, the variant allele B was statistically more frequent than the allele A in patients with an association with initial arterial high blood pressure, ESRD and class V of the Haas classification compared to those without this association (P = 0.009). The direct sequencing of exon 22 (SCR 20) of FH gene did not reveal any abnormal mutational deficiency for this factor in all patients and controls. The data did not support the hypothesis that FH is a susceptibility factor for the IgAN. However the data did show there was an association between AB (+54) exon1 MBL genotype and severe sporadic forms of this disease in Tunisian patients. Because of the small number of subjects studied, a much larger cohort of IgAN patients with varying severity of the disease and its progression would seem necessary to confirm these findings.

Atypical hemolytic uremic syndrome and mutation analysis of factor H gene in two Tunisian families.

We carried out a protein and genetic investigation of the factor H gene mutations within two families presenting with a diagnostic suspicion of atypical hemolytic uremic syndrome (aHUS). The results within the patients of the first family revealed a factor H-deficiency. Direct sequencing allowed the detection of a 4-nucleotide deletion in the factor H gene. This deletion was found as the homozygote form in the proband and as the heterozygote form in the parents. Protein and functional analyses of the complement system were normal in all members of the second family. However, the molecular investigation for the father showed the presence of an amino acid substitution in the FH gene. Unfortunately, his two affected children died without being investigated for mutations. The functional consequences of these abnormal proteins are still to be demonstrated.

Association of Fas/Apo1 gene promoter (-670 A/G) polymorphism in Tunisian patients with IBD.

AIM: To detect a possible association between the polymorphism of the (-670 A/G) Fas/Apo1 gene promoter and susceptibility to Crohn's disease (CD) and ulcerative colitis (UC) in the Tunisian population. METHODS: The (-670 A/G) Fas polymorphism was analyzed in 105 patients with CD, 59 patients with UC, and 100 controls using the polymerase chain reaction restriction fragment length polymorphism method. RESULTS: Significantly lower frequencies of the Fas -670 A allele and A/A homozygous individuals were observed in CD and UC patients when compared with controls. Analysis of (-670 A/G) Fas polymorphism with respect to sex in CD and UC showed a significant difference in A/A genotypes between female patients and controls (P corrected = 0.004 in CD patients and P corrected = 0.02 in UC patients, respectively). Analysis also showed a statistically significant association between genotype AA of the (-670 A/G) polymorphism and the ileum localization of the lesions (P corrected = 0.048) and between genotype GG and the colon localization (P corrected = 0.009). The analysis of inflammatory bowel disease patients according to clinical behavior revealed no difference. CONCLUSION: Fas-670 polymorphism was associated with the development of CD and UC in the Tunisian population.

Association between CTLA-4 gene promoter (49 A/G) in exon 1 polymorphisms and inflammatory bowel disease in the Tunisian population.

BACKGROUND/AIM: To investigate the possible association between the polymorphism of the CTLA-4 exon 1 +49 A/G and susceptibility to Crohn's disease (CD) and ulcerative colitis (UC) in the Tunisian population. METHODS: The +49 A/G dimorphism was analyzed in 119 patients with CD, 65 patients with UC, and 100 controls by the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: Significantly higher frequencies of the CTLA-4 +49A allele and A/A homozygous individuals were observed in patients with CD when compared with controls (pc = 0.0023 and pc = 0.0003, respectively). Analysis of CTLA-4 A/G polymorphism with respect to sex in CD showed a significant difference in A/A genotypes between female patients and controls (pc = 0.0001 and pc = 0.038, respectively). There were no differences in the subgroups of patients with CD. CONCLUSIONS: Forty-nine A alleles and AA genotype are associated with CD susceptibility in Tunisians. Other genes involved in the T-cell regulation remain strong candidates for IBD susceptibility and require further investigation.

Human platelet antigens polymorphisms and susceptibility of thrombosis in hemodialysis patients.

To investigate the association between the polymorphisms of human platelet antigen (HPA)-1,2,3,4,5 and susceptibility to develop thrombosis accident in arteriovenous fistula (AVF), genomic DNA of 112 hemodialysis (HD) patients and 100 healthy blood donors were genotyped by PCR-SSP. The patients were classified into 2 groups: G1 included 54 HD patients presented at least one thrombotic episode on the level of the AVF, and G2 included 58 HD patients without any episode of thrombosis. The allelic frequencies of HPA-1, 2, 3, and 5 among patients and controls did not reveal significant differences. However, the HPA-4b allele was significantly more frequent in G1 than in controls or in G2 patients (23.1% vs. 11.5% and 0.9%, respectively), p<0.01 and p<0.001. The genotype distribution of HPA-4 polymorphism reveals that the HPA-4a4b genotype was more frequent in G1 patients (23/54: 42.6%) than in all HD patients (25/112: 22.3%) or in G2 patients (1/58: 1.72%) (p<0.001, odds ratio: 45.6). Among 24 HD patients with HPA-4a4b genotype, 23 (96%) developed at least 1 or more thrombotic episode on the level of their AVF. However, 30 patients (34.5%) among 87 HD patients with HPA-4a4a genotype presented thrombotic episode (p<0.001). These results reveal a significant association between HPA-4a4b and thrombosis, and it is likely that HPA polymorphisms could be useful markers for potential risk of thrombosis in hemodialysis.

Hepatitis B virus genotypes and precore/core-promoter mutations in Tunisian patients with chronic hepatitis B virus infection.

OBJECTIVE: The aim of this study was to determine the frequency of genotype and precore/core-promoter mutations in chronic hepatitis B virus (HBV) infected individuals in Tunisia. METHODS: We studied 164 Tunisian patients (38 HBeAg-positive and 126 HBeAg-negative) with chronic HBV infection. Genotypes and precore/core-promoter mutations were studied using Inno-LiPA and Multiplex-PCR and PCR-RFLP methodology. RESULTS: Alanine aminotransferase (ALT) levels were higher in HBeAg-positive compared with HBeAg-negative patients (p<0.05). Patients with HBeAg-positive chronic hepatitis B were younger than HBeAg-negative chronic hepatitis B patients. The 164 genotypes were distributed as follows: 1 genotype A (0.6%), 1 genotype B (0.6%), 3 genotype C (1.82%), 139 genotype D (84.75%), and 20 mixed genotypes (12.2%). In the precore region (41.5%) of the patients had exclusively PC mutant and (50.9%) had a mixture of wild-type and variant sequences. PC variant was more commonly found in HBeAg-negative patients than in HBeAg-positive patients (94.5% vs. 87.8%), respectively. The mutations in the core promoter were more common in HBeAg-negative patients (65.4%) than in HbeAg-positive patients (18.2%). These results indicate that genotype D is predominant in Tunisia. Precore mutation occurred invariably among HBeAg-positive and HBeAg-negative patients, whereas core-promoter mutations were more frequently found in HBeAg-negative patients. CONCLUSION: Analysis of these mutants may prove useful for clinical evaluation and choice of therapy.

Role of immune system, apoptosis and angiogenesis in pathogenesis of rheumatoid arthritis and joint destruction, a systematic review.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory disorder of unknown cause that is notorious for the chronic polyarticular synovial inflammation and progressive destruction of affected joints. Understanding the pathogenesis of RA provides the basis for optimal management of that disease in patients. The pathogenesis of RA was largely explored in many studies in human as much as in mice models with collagen II induced arthritis, nevertheless the pathogenesis puzzle is still incomplete. AIM: The aim of this systematic review was to collect the results of many observations and to put them down into an original story of RA set up. METHODS: An exhaustive electronic and library search of the relevant literature was carried out through "science direct" and "interscience wiley" web sites. The key words used for the search were "rheumatoid arthritis", "pathogenesis", "apoptosis", "angiogenesis", "immune response" and "joint destruction". RESULTS: The suspected responsible antigen isn't yet determined although the great specificity of anti-CCP antibodies suggests that this antigen carries probably many citrullinated residues. The immuno-pathogenesis of RA involves both the innate and the adaptive immune system. In the other hand, apoptosis defect contribute to hyperplasia of rheumatoid synovium and in extended half life of fibroblast like synoviocytes (FLS), neutrophils and many other cells implied in rheumatoid synovitis. Hyperplasia of synovium leads to ischemia and that results in neo-angiogenesis with increase of proangiogenic factors such as VEGF. The last part of the pathogenesis of RA is the joint destruction resulting from increased MMP production and activation of osteoclasts which leads to the breakup of cartilage and to bone damage.