| 51. |
- Jaatinen, Taina, et al.
(författare)
-
Total C4B deficiency due to gene deletion and gene conversion in a patient with severe infections
- 2003
-
Ingår i: Clinical and Diagnostic Laboratory Immunology. - 1071-412X. ; 10:2, s. 195-201
-
Tidskriftsartikel (refereegranskat)abstract
- Deficiencies of the early components of the classical complement pathway impair the actions of innate and humoral immunity and may lead to increased susceptibility to infections. We have studied the genetic basis of total C4B deficiency in a Finnish patient with recurrent meningitis, chronic fistulas and abscesses. The maternal chromosome carried a four-gene deletion including the C4B gene, and a conversion from C4B to C4A gene was found on the paternal chromosome resulting in complete deficiency of C4B. In the converted C4A gene, mutation screening did not reveal any amino acid changes or prominent mutations, yet a large number of nucleotide variations were found. Further, the patient was heterozygous for structural deficiency of mannan binding lectin (MBL) associating with medium levels of serum MBL. Our data provides new information on the genetic instability of the C4 gene region, and on the association of homozygous C4B deficiency and variant MBL genotype with increased susceptibility to recurrent and chronic infections. Importantly, plasma therapy induced a prompt clinical cure with long-term effects.
|
|
| 52. |
- Jansson, Kjell, 1958-, et al.
(författare)
-
Intraperitoneal cytokine response after major surgery : higher postoperative intraperitoneal versus systemic cytokine levels suggest the gastrointestinal tract as the major source of the postoperative inflammatory reaction
- 2004
-
Ingår i: American Journal of Surgery. - : Elsevier BV. - 0002-9610 .- 1879-1883. ; 187:3, s. 372-377
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cytokine response is an important factor in the development of shock and organ failure. The aim of this study was to investigate intraperitoneal (peritoneal) and venous (systemic) postoperative cytokine release after major surgery.METHODS: Major abdominal surgery was performed in 19 patients. Preoperative systemic measurements and postoperative systemic and peritoneal measurements of C-reactive protein (CRP) and the cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin (IL-6), and IL-10 were performed.RESULTS: Significantly higher TNF-alpha, IL-6, and IL-10 peritoneal values were recorded compared with systemic values, whereas peritoneal CRP was significantly decreased. CRP increased significantly over time, whereas postoperative values of IL-6, IL-10, and peritoneal TNF-alpha decreased. Systemic TNF-alpha was constant over time, but values after emergent abdominal surgery showed a more extensive response. An additional effect of surgery and emergent abdominal disease was seen in increased TNF-alpha and IL-10 levels.CONCLUSIONS: Compared with systemic cytokines, peritoneal cytokines respond extensively after major surgery, indicating that measurement of peritoneal cytokines is a more sensible method to determine postoperative inflammatory reaction. A normal postoperative course is characterized by decreasing levels of peritoneal cytokines.
|
|
| 53. |
- Jansson, Kjell, 1958-, et al.
(författare)
-
Postoperative on line monitoring with intraperitoneal microdialysis is a sensitive clinical method for measuring increased anaerobic metabolism that correlates to the cytokine response
- 2004
-
Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 39:5, s. 434-439
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Visceral ischaemia and cytokine release are early stages in the development of shock and multiorgan failure. Because of lack of methods to measure anaerobic metabolism or visceral hypoxia in the early phase, diagnosis is not usually established until shock and organ failure are evident. Methods: Nineteen patients were studied postoperatively after major abdominal gastrointestinal surgery. A microdialysis catheter was placed intraperitoneally before closure of the abdomen. Analysis of glucose, pyruvate and lactate was performed every second hour and the ratio between lactate and pyruvate was calculated. Peritoneal fluid was collected from a peritoneal drainage for analysis of tumour necrosis factor alpha (TNF‐α) and interleukin 10 (IL‐10). Results: Sixteen of the patients had a normal postoperative course; the lactate/pyruvate ratio started at the level of 20 immediately postoperatively and decreased significantly during the first 45 postoperative hours (P = 0.007). A similar pattern was recorded for peritoneal TNF‐α, which decreased correspondingly (P = 0.003). A correlation coefficient of 0.303 (P < 0.001) between lactate/pyruvate ratio and TNF‐α was found. After an initial short increase, IL‐10 decreased over time (P < 0.001). Three of the patients had abnormalities in the microdialysis results, cytokines and clinical outcome. These patients are presented separately. Conclusions: A normal postoperative course results in a decrease in the intraperitoneal lactate/pyruvate ratio, TNF‐α and IL‐10. A correlation between the intraperitoneal lactate/pyruvate ratio and TNF‐α was found which suggests that intraperitoneal microdialysis is a sensitive, indirect method in analysing the postoperative intraperitoneal inflammatory response. A complicated postoperative course was preceded by increase of the peritoneal lactate/pyruvate ratio interpreted as splanchnic hypoxia and also an increased TNF‐α level.
|
|
| 54. |
- Johanneson, B, et al.
(författare)
-
A comparison of genome-scans performed in multicase families with systemic lupus erythematosus from different population groups
- 1999
-
Ingår i: Journal of Autoimmunity. - : Elsevier BV. - 0896-8411. ; 13, s. 137-
-
Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus is a disease of unknown etiology. Multiple genetic factors are believed to be involved in its pathogenesis. In addition, and due to genetic heterogeneity, these factors and/or their combinations may be different in different ethnic groups, while some might be shared between populations. We have performed genome scans in multicase families from three different population groups, two from Northern Europe, with a high degree of homogeneity, and the third from a recently admixed population of Mexican Mestizos. Although our family material is relatively small, the results presented here show that using family sets from well defined populations are sufficient to detect susceptibility loci for SLE. Our results also reveal the chromosomal regions most likely to contain susceptibility genes for SLE.
|
|
| 55. |
- Jönsen, Andreas, et al.
(författare)
-
Analysis of HLA DR, HLA DQ, C4A, FcgammaRIIa, FcgammaRIIIa, MBL, and IL-1Ra allelic variants in Caucasian systemic lupus erythematosus patients suggests an effect of the combined FcgammaRIIa R/R and IL-1Ra 2/2 genotypes on disease susceptibility.
- 2004
-
Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1465-9905. ; 6:6, s. 557-562
-
Tidskriftsartikel (refereegranskat)abstract
- Dysfunction in various parts of immune defence, such as immune response, immune complex clearance, and inflammation, has an impact on pathogenesis in systemic lupus erythematosus (SLE). We hypothesised that combinations of common variants of genes involved in these immune functions are associated with susceptibility to SLE. The following variants were analysed: HLA DR3, HLA DQ2, C4AQ0, Fcgamma receptor IIa (FcgammaRIIa) genotype R/R, Fcgamma receptor IIIa (FcRgammaIIIa) genotype F/F, mannan-binding lectin (MBL) genotype conferring a low serum concentration of MBL (MBL-low), and interleukin-1 receptor antagonist (IL-1Ra) genotype 2/2. Polymorphisms were analysed in 143 Caucasian patients with SLE and 200 healthy controls. HLA DR3 in SLE patients was in 90% part of the haplotype HLA DR3-DQ2-C4AQ0, which was strongly associated with SLE (odds ratio [OR] 2.8, 95% CI 1.7-4.5). Analysis of combinations of gene variants revealed that the strong association with SLE for HLA DR3-DQ2-C4AQ0 remained after combination with FcgammaRIIa R/R, FcgammaRIIIa F/F, and MBL-low (OR>2). Furthermore, the combination of the FcgammaRIIa R/R and IL-1Ra 2/2 genotypes yielded a strong correlation with SLE (OR 11.8, 95% CI 1.5-95.4). This study demonstrates that certain combinations of gene variants may increase susceptibility to SLE, suggesting this approach for future studies. It also confirms earlier findings regarding the HLA DR3-DQ2- C4AQ0 haplotype.
|
|
| 56. |
- Jönsen, Andreas, et al.
(författare)
-
Association between SLE nephritis and polymorphic variants of the CRP and Fc gamma RIIIa genes
- 2007
-
Ingår i: Rheumatology. - : Oxford University Press (OUP). - 1462-0332 .- 1462-0324. ; 46:9, s. 1417-1421
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives. To study the relationship between clinical manifestations in systemic lupus erythematosus (SLE) with polymorphisms in suggested susceptibility genes encoding Fc gamma RIIa, Fc gamma RIIIa, Fc gamma RIIIb, CRP and IL-1Ra. Methods. Genetic polymorphisms were analysed in 323 unrelated SLE patients and 200 healthy blood donors. The genotype frequencies were compared between clinical subsets of SLE patients, as well as with healthy controls. Clinical manifestations included the ACR classification criteria. Nephritis was further classified according to WHO class on renal biopsy. Results. Presence of a CRP4 A-allele was associated with SLE nephritis (P< 0.01) and inversely correlated with arthritis (P < 0.01), when comparing within the SLE group. The Fc gamma RIIIa F/F genotype was also associated with nephritis (WHO class III and IV, P=0.04 for the SLE group) and in combination with the CRP4 A-allele a stronger association was noted (P<0.001). Furthermore, the Fc gamma RIIIb NA2/NA2 genotype was associated with butterfly rash (P< 0.01). An association was found between seizures and the presence of both the Fc gamma RIIa R/R and the Fc gamma RIIIa F/F genotypes (P< 0.01) and an inverse correlation between serositis and the CRP4 A-allele when present together with the IL-1Ra 2-allele (P=0.01). Furthermore, a combination of the Fc gamma RIIa R/R genotype and CRP4 A-allele was associated with lymphopenia (P= 0.02) and a similar result was found for the combination of Fc gamma RIIIa F/F and Fc gamma RIIIb NA2/NA2 (P= 0.04). Conclusions. Polymorphic variants of the CRP and Fc gamma-receptor genes are associated with the clinical phenotype in SLE. Our findings suggest an immune complex-mediated pathogenesis in nephritis and seizures, while development of arthritis may depend on other pathogenetic pathways.
|
|
| 57. |
- Jönsen, Andreas, et al.
(författare)
-
Gene-environment interactions in the aetiology of systemic lupus erythematosus
- 2007
-
Ingår i: Autoimmunity. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; 40:8, s. 613-617
-
Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus (SLE) is a disease that displays a multitude of symptoms and a vast array of autoantibodies. The disease course may vary substantially between patients. The current understanding of SLE aetiology includes environmental factors acting on a genetically prone individual during an undetermined time period resulting in autoimmunity and finally surpassing that individual's disease threshold. Genetic differences and environmental factors may interact specifically in the pathogenetic processes and may influence disease development and modify the disease course. Identification of these factors and their interactions in the pathogenesis of SLE is vital in understanding the disease and may contribute to identify new treatment targets and perhaps also aid in disease prevention. However, there are several problems that need to be overcome, such as the protracted time frame of environmental influence, time dependent epigenetic alterations and the possibility that different pathogenetic pathways may result in a similar disease phenotype. This is mirrored by the relatively few studies that suggest specific gene-environment interactions. These include an association between SLE diagnosis and glutathion S-transferase gene variants combined with occupational sun exposure as well as variants of the N-acetyl transferase gene in combination with either aromatic amine exposure or hydralazine. With increased knowledge on SLE pathogenesis, the role of environmental factors and their genetic interactions may be further elucidated.
|
|
| 58. |
- Jönsen, Andreas, et al.
(författare)
-
Genetically determined mannan-binding lectin deficiency is of minor importance in determining susceptibility to severe infections and vascular organ damage in systemic lupus erythematosus.
- 2007
-
Ingår i: Lupus. - : SAGE Publications. - 0961-2033 .- 1477-0962. ; 16:4, s. 245-253
-
Tidskriftsartikel (refereegranskat)abstract
- Deficiency of mannan-binding lectin (MBL) has been reported to impact susceptibility to severe nfections and atherosclerosis in systemic lupus erythematosus (SLE). In this study, MBL gene polymorphisms were analysed in 143 SLE patients and the frequency of severe infections and organ damage according to SLICC/ACR Damage Index regarding cerebrovascular accidents, angina pectoris, coronary by-pass surgery, myocardial infarction and peripheral arterial disease leading to significant tissue loss, were recorded during a mean follow-up time of 15 years from diagnosis. In a multiple logistic regression model, smoking (P = 0.001), hypertension (P = 0.030), alcohol intake (P = 0.027) and higher triglyceride concentration (P = 0.026) were associated with cerebrovascular, cardiovascular and peripheral arterial organ damage (CPAD), while the association with MBL deficiency did not reach significance (P = 0.098). Alcohol intake (> 15 g/month) was inversely correlated with CPAD (OR = 0.29, 95%Cl 0.096-0.87). MBL deficiency was not significantly more common in SLE patients with severe infections in a multivariate analysis (P > 0.3). In conclusion, classical risk factors such as smoking, hypertension, low alcohol intake and elevated triglyceride concentration were relatively more important for development of CPAD than MBL deficiency in SLE. Furthermore, MBL deficiency did not contribute to development of major infections in SLE.
|
|
| 59. |
- Jönsen, Andreas, et al.
(författare)
-
Mitochondrial DNA polymorphisms are associated with susceptibility and phenotype of systemic lupus erythematosus.
- 2009
-
Ingår i: Lupus. - : SAGE Publications. - 0961-2033 .- 1477-0962. ; 18:4, s. 309-312
-
Tidskriftsartikel (refereegranskat)abstract
- The objective of this study was to investigate the possible association between mitochondrial DNA polymorphisms and systemic lupus erythematosus (SLE). A cohort from the Department of Rheumatology, Lund University Hospital, Sweden, consisting of 166 unrelated SLE patients was investigated as well as 190 unrelated healthy blood donors. Mean age at SLE diagnosis was 39 years (range 10-83) and mean follow-up time was 16 years (range 1-44). There were 87% women among the lupus patients, and the control group consisted of 98 women and 92 men from the same geographical area and with a similar age and ethnicity. The mtDNA SNP nt16189C was associated with SLE (OR = 1.98, 95% CI 1.04-3.78, P = 0.05). In addition, SNP nt13708A was associated with SLE in males (OR = 3.46, 95% CI 1.08-11.1, P = 0.04), although the number of male patients was low. Furthermore, SNP nt10398A was associated with secondary anti-phospholipid syndrome (P = 0.017, OR 8.2, 95% CI 1.1-63). In conclusion, in this study, we have for the first time investigated the possible association between SLE disease and mitochondrial DNA polymorphisms. Altogether, these novel results suggest that mtDNA polymorphisms may be associated with development of SLE and may potentially be of importance in SLE pathogenesis.
|
|
| 60. |
- Jönsen, Andreas, et al.
(författare)
-
Mutations in genes encoding complement inhibitors CD46 and CFH affect the age at nephritis onset in patients with systemic lupus erythematosus
- 2011
-
Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 13, s. R206-
-
Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Inherited deficiencies of several complement components strongly predispose to systemic lupus erythematosus (SLE) while deficiencies of complement inhibitors are found in kidney diseases such as atypical hemolytic uremic syndrome (aHUS). METHODS: The exons of complement inhibitor genes: CD46 and CFH (factor H) were fully sequenced using Sanger method in SLE patients with nephritis originating from two cohorts from southern and mid Sweden (n = 196). All identified mutations and polymorphisms were then analyzed in SLE patients without nephritis (n = 326) and healthy controls (n = 523). RESULTS: We found non-synonymous, heterozygous mutations in CFH in 6.1% patients with nephritis in comparison to 4.0% and 5.4% in patients without nephritis and controls, respectively. No associations of SLE or nephritis with common variants in CFH (V62I/Y402H/E936D) were found. Furthermore, we found two non-synonymous heterozygous mutations in CD46 in SLE patients but not in controls. The A353V polymorphism, known to affect function of CD46, was found in 6.6% of nephritis patients vs 4.9% and 6.1% of the non-nephritis SLE patients and controls. The presence of mutations in CD46 and CFH did not predispose to SLE or nephritis but was associated with earlier onset of nephritis. Furthermore, we found weak indications that there is one protective and one risk haplotype predisposing to nephritis composed of several polymorphisms in non-coding regions of CD46, which were previously implicated in aHUS. CONCLUSION: SLE nephritis is not associated with frequent mutations in CFH and CD46 as found in aHUS but these may be modifying factors causing earlier onset of nephritis.
|
|
