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Studies on Neuropsychiatric Manifestations and Genetic Factors in Systemic Lupus Erythematosus

Jönsen, Andreas LU (2006)
Abstract
Background: Systemic Lupus Erythematosus (SLE) is an autoimmune disease encompassing a wide range of symptoms that can emanate from pathology in virtually any organ system. Severe SLE includes involvement of the central nervous system and kidneys. One of the hallmarks of the disease is a multitude of autoantibodies, indicating a breakdown in self tolerance. The corresponding antigens have been found to be exposed in cells undergoing apoptosis. Increased rate of apoptosis and an impaired clearance machinery for apoptotic material leading to secondary necrosis have been put forward as potential mechanisms by which a genetically prone individual develop an immune response to self antigens. Inherent dysregulation of tolerance and the immune... (More)
Background: Systemic Lupus Erythematosus (SLE) is an autoimmune disease encompassing a wide range of symptoms that can emanate from pathology in virtually any organ system. Severe SLE includes involvement of the central nervous system and kidneys. One of the hallmarks of the disease is a multitude of autoantibodies, indicating a breakdown in self tolerance. The corresponding antigens have been found to be exposed in cells undergoing apoptosis. Increased rate of apoptosis and an impaired clearance machinery for apoptotic material leading to secondary necrosis have been put forward as potential mechanisms by which a genetically prone individual develop an immune response to self antigens. Inherent dysregulation of tolerance and the immune response augment and perpetuate the situation generating autoreactive B- and T-cells, which together with autoantibodies and immune complexes mediate tissue inflammation with subsequent development of clinical symptoms. In this thesis, studies on neuropsychiatric involvement in SLE (NPSLE) and the genetic contribution to susceptibility and phenotypic expression of SLE are presented.



Results: In paper I, an association was seen between NPSLE and worse prognosis measured as working incapacity and extent of organ damage, but not with increased mortality, as compared to non-NPSLE patients. In paper II, the conclusion is drawn that cerebrospinal fluid analyses of cytokines and autoantibodies may be of limited value in NPSLE diagnosis, while increased concentrations of anti-ribosomal P protein antibodies in serum could constitute a marker for SLE psychosis. In paper III, polymorphic variants of genes with well-documented roles in different parts of SLE pathogenesis were studied with the hypothesis that gene variant combinations could be informative regarding susceptibility for and pathogenesis in SLE. The extended haplotype HLA DR3-DQ2-C4AQ0 was more common in SLE patients than in controls (p<0.01). Furthermore, an increased prevalence of the combination of the IL-1 Ra 2/2 and the Fc?RIIa R/R genotypes was found in SLE patients compared to healthy controls (p<0.01). In paper IV, several genetic variants were found to influence disease phenotype. Thus, presence of a CRP4 A-allele was associated with SLE nephritis (p<0.01) and inversely correlated with arthritis (p<0.01). Furthermore, the Fc?RIIIa F/F genotype correlated with WHO class III and IV nephritis. Presence of anti-dsDNA or anti-C1q antibodies did not have an additional impact on the genetic susceptibility to nephritis. Additionally, the Fc?RIIIb NA2/NA2 genotype was associated with butterfly rash (p<0.01). Combinations of genotypes revealed an association between seizures and the presence of both the Fc?RIIa R/R and the Fc?RIIIa F/F genotypes (p<0.01), as well as an inverse correlation between serositis and the CRP4 A-allele when present together with the IL-1Ra 2-allele. In paper V, the impact of deficiency in the complement protein mannan-binding lectin (MBL) on cerebrovascular, cardiovascular and peripheral arterial organ damage (CPAD) and severe infections was studied. In a multiple logistic regression model smoking (p=0.001), hypertension (p=0.03), alcohol intake (p=0.027) and serum triglyceride concentrations (p=0.026) were associated with CPAD, while MBL deficiency did not reach significance (p=0.098). Alcohol intake (>15 g/month) was inversely correlated with CPAD (OR=0.29, 95%CI 0.096-0.87). Pneumonia and severe infections were not more common in SLE patients with MBL deficiency. There was a significant association between treatment with high-dose glukocorticoids and presence of severe infections (p=0.008). Treatment with cytostatic drugs was also more common in patients with these severe infections, but the correlation did not reach statistical significance (p=0.054).



Conclusions: Neuropsychiatric involvement is a severe manifestation of SLE, but is heterogeneous and diagnostic tests in CSF are of limited value. Combination of genetic variants can be of importance in determining SLE susceptibility and the contribution of polymorphic genes to disease phenotype is substantial. (Less)
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author
supervisor
opponent
  • Overlæge, dr.med. Jacobsen, Søren, Reumatologisk klinik, Rigshospitalet, København, Danmark
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Skeleton, Genetics, Systemic Lupus Erythematosus, Neuropsychiatric, rheumatology locomotion, Skelett, muskelsystem, reumatologi, muscle system
pages
128 pages
publisher
Department of Clinical Sciences, Lund University
defense location
Reumatologiska klinikens föreläsningssal, Universitetssjukhuset i Lund
defense date
2006-09-11 09:00:00
ISBN
91-85559-14-8
language
English
LU publication?
yes
additional info
A Jönsen, AA Bengtsson, O Nived, B Ryberg and G Sturfelt. 2002. Outcome of neuropsychiatric systemic lupus Erythematosus within a defined Swedish population: increased morbidity but low mortality. Rheumatology, vol 41 pp 1308-1312.
A Jönsen, AA Bengtsson, O Nived, B Ryberg, L Truedsson, L Rönnblom, GV Alm and G Sturfelt. 2003. The heterogeneity of neuropsychiatric systemic lupus erythematosus is reflected in lack of association with cerebrospinal fluid profiles. Lupus, vol 12 pp 846-850.
A Jönsen, AA Bengtsson, G Sturfelt and L Truedsson. 2004. Analysis of HLA DR, HLA DQ, C4A, Fc?RIIa, Fc?RIIIa, MBL and IL-1Ra allelic variants in Caucasian systemic lupus Erythematosus patients suggests an effect of the combined Fc?RIIa R/R and IL-1Ra 2/2 genotypes on disease susceptibility. Arthritis Res Ther, vol 6 pp 557-562.
A Jönsen, I Gunnarsson, B Gullstrand, E Svenungsson, AA Bengtsson, IE Lundberg, L Truedsson and G Sturfelt. . Association between SLE nephritis and polymorphic variants of the CRP and Fc?RIIIa genes. (submitted)
A Jönsen, AA Bengtsson, B Gullstrand, N Güner, O Nived, L Truedsson and G Sturfelt. . Genetically determined mannan-binding lectin deficiency is of minor importance in determining susceptibility to severe infections and vascular organ damage in systemic lupus erythematosus. (submitted)
id
91b21cc8-336d-4009-884b-df15ac3ab778 (old id 547034)
date added to LUP
2016-04-01 15:57:51
date last changed
2018-11-21 20:37:42
@phdthesis{91b21cc8-336d-4009-884b-df15ac3ab778,
  abstract     = {{Background: Systemic Lupus Erythematosus (SLE) is an autoimmune disease encompassing a wide range of symptoms that can emanate from pathology in virtually any organ system. Severe SLE includes involvement of the central nervous system and kidneys. One of the hallmarks of the disease is a multitude of autoantibodies, indicating a breakdown in self tolerance. The corresponding antigens have been found to be exposed in cells undergoing apoptosis. Increased rate of apoptosis and an impaired clearance machinery for apoptotic material leading to secondary necrosis have been put forward as potential mechanisms by which a genetically prone individual develop an immune response to self antigens. Inherent dysregulation of tolerance and the immune response augment and perpetuate the situation generating autoreactive B- and T-cells, which together with autoantibodies and immune complexes mediate tissue inflammation with subsequent development of clinical symptoms. In this thesis, studies on neuropsychiatric involvement in SLE (NPSLE) and the genetic contribution to susceptibility and phenotypic expression of SLE are presented.<br/><br>
<br/><br>
Results: In paper I, an association was seen between NPSLE and worse prognosis measured as working incapacity and extent of organ damage, but not with increased mortality, as compared to non-NPSLE patients. In paper II, the conclusion is drawn that cerebrospinal fluid analyses of cytokines and autoantibodies may be of limited value in NPSLE diagnosis, while increased concentrations of anti-ribosomal P protein antibodies in serum could constitute a marker for SLE psychosis. In paper III, polymorphic variants of genes with well-documented roles in different parts of SLE pathogenesis were studied with the hypothesis that gene variant combinations could be informative regarding susceptibility for and pathogenesis in SLE. The extended haplotype HLA DR3-DQ2-C4AQ0 was more common in SLE patients than in controls (p&lt;0.01). Furthermore, an increased prevalence of the combination of the IL-1 Ra 2/2 and the Fc?RIIa R/R genotypes was found in SLE patients compared to healthy controls (p&lt;0.01). In paper IV, several genetic variants were found to influence disease phenotype. Thus, presence of a CRP4 A-allele was associated with SLE nephritis (p&lt;0.01) and inversely correlated with arthritis (p&lt;0.01). Furthermore, the Fc?RIIIa F/F genotype correlated with WHO class III and IV nephritis. Presence of anti-dsDNA or anti-C1q antibodies did not have an additional impact on the genetic susceptibility to nephritis. Additionally, the Fc?RIIIb NA2/NA2 genotype was associated with butterfly rash (p&lt;0.01). Combinations of genotypes revealed an association between seizures and the presence of both the Fc?RIIa R/R and the Fc?RIIIa F/F genotypes (p&lt;0.01), as well as an inverse correlation between serositis and the CRP4 A-allele when present together with the IL-1Ra 2-allele. In paper V, the impact of deficiency in the complement protein mannan-binding lectin (MBL) on cerebrovascular, cardiovascular and peripheral arterial organ damage (CPAD) and severe infections was studied. In a multiple logistic regression model smoking (p=0.001), hypertension (p=0.03), alcohol intake (p=0.027) and serum triglyceride concentrations (p=0.026) were associated with CPAD, while MBL deficiency did not reach significance (p=0.098). Alcohol intake (&gt;15 g/month) was inversely correlated with CPAD (OR=0.29, 95%CI 0.096-0.87). Pneumonia and severe infections were not more common in SLE patients with MBL deficiency. There was a significant association between treatment with high-dose glukocorticoids and presence of severe infections (p=0.008). Treatment with cytostatic drugs was also more common in patients with these severe infections, but the correlation did not reach statistical significance (p=0.054).<br/><br>
<br/><br>
Conclusions: Neuropsychiatric involvement is a severe manifestation of SLE, but is heterogeneous and diagnostic tests in CSF are of limited value. Combination of genetic variants can be of importance in determining SLE susceptibility and the contribution of polymorphic genes to disease phenotype is substantial.}},
  author       = {{Jönsen, Andreas}},
  isbn         = {{91-85559-14-8}},
  keywords     = {{Skeleton; Genetics; Systemic Lupus Erythematosus; Neuropsychiatric; rheumatology locomotion; Skelett; muskelsystem; reumatologi; muscle system}},
  language     = {{eng}},
  publisher    = {{Department of Clinical Sciences, Lund University}},
  school       = {{Lund University}},
  title        = {{Studies on Neuropsychiatric Manifestations and Genetic Factors in Systemic Lupus Erythematosus}},
  year         = {{2006}},
}