Cytotoxic T lymphocyte antigen 4 (CTLA-4) dimorphism in patients with systemic lupus erythematosus.

OBJECTIVE: Genetic susceptibility to systemic lupus erythematosus (SLE) is conferred not only by various genes within the major histocompatibility complex (MHC) region, but also by several other non-MHC linked genes. The negatively signalling molecule CTLA-4 is involved in establishing and maintaining of peripheral T cell tolerance, which controls T cell activation and reactivity. Its attenuating action helps to prevent an inappropriate initiation of T cell responses to self antigens and to terminate ongoing T cell responses. We tested if there was an association between CTLA-4 and SLE, a disease with B and T cell hyperreactivity and impaired peripheral T cell tolerance. METHODS: Using the polymerase chain reaction--restriction fragment length polymorphism method with Bbv I digestion, we assessed an exon 1 transition dimorphism (49 A/G) of the CTLA-4 gene in 102 SLE patients and in 76 healthy controls. RESULTS: The distribution of CTLA-4 exon 1 genotypes in the SLE group was significantly different from that in the controls (chi 2 = 6.178, p < 0.05). 17.6% of the SLE patients were G/G homozygotes compared to 5.3% of the controls; 36.3% were A/G heterozygotes vs 40.8% of controls; and 46.1% were A/A homozygotes vs 53.9% of the controls. The frequency of the G allele was significantly higher in SLE patients (35.8%) than in controls (25.7%; chi 2 = 4.142, p = 0.042). CONCLUSION: Our results indicate that the non-MHC linked CTLA-4 gene could confer susceptibility in SLE, as it does in various other autoimmune diseases (Hashimoto thyroiditis, Graves' disease, IDDM).

Association between systemic lupus erythematosus and insertion/deletion polymorphism of the angiotensin converting enzyme (ACE) gene.

OBJECTIVE: ACE takes part in the renin-angiotensin and kallikrein-kininogen systems by creating angiotensin-II and inactivating bradykinin. ACE gene insertion/deletion polymorphism is associated with the level of circulating enzymes--subjects with the DD genotype have higher levels of circulating ACE than subjects with the II genotype and show an increased tendency towards impaired vascular function and structure. Patients with systemic lupus erythematosus (SLE) suffer from differentially expressed vascular pathology. We attempted to determine whether the type of ACE polymorphism could contribute to this pathology. METHODS: 101 SLE patients fulfilling the ACR criteria were investigated. The I/D polymorphism was ascertained by PCR, followed by electrophoresis of the amplified fragments and UV visualization. RESULTS: The frequency of the D allele was higher in the SLE group (0.623) than in the controls (0.520) (chi 2 test, p < 0.025). The distribution of the ACE genotype in SLE group was different from that in the control group (p < 0.05). An association between the DD genotype and visceral damage (p < 0.006) was observed. CONCLUSION: Our results suggest that in the multifactorially determined vascular pathology of SLE, changes associated with I/D polymorphism could influence vessel wall inflammation (monocyte adhesion and activation with cytokine release, T-lymphocyte metabolism), a tendency towards vascular impairment (neointimal proliferation, vasospasm, platelet activation, myocyte proliferation) and lead to the subsequent ischemia. The ACE gene could serve as the visceral damage indicator in SLE.

[Selected parameters of lipoprotein metabolism in cerebrovascular diseases]. / Vybrané parametre metabolizmu lipoproteínov pri cerebrovaskulárnych ochoreniach.

In series of patients with stroke, selected by random (n = 68), mean age 62.44 +/- 9.12 years (range 39-82 yrs), there were 23 females (33.8%), mean age 65.43 +/- 10.11 yrs and 45 males (66.2%) mean age 60.8 +/- 8.3 yrs. Lp(a) reference values have been obtained from a group of 283 healthy individuals (age ranging from 15 to 65 years). The cholesterol, triacyglycerol, Apo B reference values come from the database of the Department of Clinical Biochemistry. There were 52 hypoxemic stroke patients in the whole observed group. Triacylglycerol serum level TAG < or = 2.89 mmol/l was observed in 47 cases (90.3%), the serum level TAG > 2.89 mmol/l was present in 5 cases (9.7%). The occurrence of TAG normal serum level was significantly more frequent than its pathologic increase (p < 0.001). Apolipoprotein Apo B < or = 1.67 g/l serum level was present in 41 (78.8%) and Apo B > 1.67 g/l in 11 (21.2%) cases (p < 0.001). Apo B < or = 1.67 g/l serum levels in 23 cases (82.1%) and Apo B > 1.67 g/l in 5 cases (18%) were observed among the stroke diabetes mellitus patients (n = 28)--statistic difference in 1/1000 level. In the total hypoxemic stroke group (n = 52), Lp(a) < or = 0.278 g/l was observed in 44 cases (84.6%), Lp(a) > 0.278 g/l serum level was present in 8 cases (15.4%)/ - p < 0.001. According to EASD consensus the serum level of Lp(a) = 0.278 g/l has been considered as "cut-off limit". Similar distribution of Lp(a) serum levels was observed in the diabetes mellitus stroke group (n = 28), the ischemic heart group (n = 54), the group with aortosclerosis (n = 16) and in the group with arterial hypertension (n = 50). Elevated TAG serum levels were not in correlation with the number of sites where atherosclerotic changes were proved by arteriography, ultrasound investigation e.g. in the extracranial brain supplying arteries. Elevated Lp(a) serum levels did not correlate with the stage of ischemic heart disease and they correlated with the stage of functional CNS defect in arterial hypertension and atherosclerosis. Metabolic disorders of lipoprotein and apolipoprotein, namely genomic transcription of lipoprotein seem to be more significant risk stroke factors, but, if they are present, they contribute to the occurrence of arteriosclerosis of some larger arteries. Elevated Lp(a) serum levels did not correlate with the stage of the heart ischemic disease and aortosclerosis, but they correlate with the stage of functional CNS defect due to arteriosclerosis and arterial hypertension, hence the increase in Lp(a) serum level as an indicator of arteriosclerotic evolution of cerebral arteries is significant. Our results, hence, do confirm a common supposition for Lp(a) serum level as an independent arteriosclerotic risk factor of the brain arteries. (Fig. 7, Tab. 1, Ref. 22.)