Study of the role of CD40 / CD40-L interaction in the pathogenesis of rheumatoid arthritis [RA]

CD40/CD40 ligand [CD4O/CD4O-L] interaction has pleiotropic effects in a variety of cells and biological processes including immune response. Within the immune system, these molecules represent a critical link between its humoral and cellular arms. Numerous autoimmune diseases are associated with CD40/CD40-L interaction. CD40 is a cell surface receptor that belongs to the tumor necrosis factor-receptor [TNF-R] family, and that was first identified and functionally characterized on B- lymphocytes. CD40 ligand [CD40-L] or [CD154], a member of the TNF superfamily, is a cell membrane molecule expressed on activated CD4+ T-lymphocytes. Therefore, it is now thought that CD40/CD40-L interactions play a more important role in autoimmune disease regulation. The aim of the present work was to measure the level of surface expression of CD40-L and CD40 on PB lymphocytes of rheumatoid arthritis [RA] patients and to correlate it with clinical and laboratory data and with disease activity. To achieve this goal, 30 patients with RA [Group I] who were further subdivided into group IA [15 patients with active RA] and group IB [15 patients with inactive RA], in addition to 20 healthy control volunteers [group II] were studied. All studied groups were subjected to routine laboratory investigations including, complete blood count [CBC], ESR, C-reactive protein [CRP], rheumatoid factor [RF] measured by latex test and by Rose-Waaler test. Surface CD40-L and CD40 expression on lymphocytes was measured by flowcytometry on peripheral blood [PB] of all studied groups. Statistical analysis of the results of the present study showed that surface expression of CD40-L on PB T-lymphocytes was significantly higher in RA compared to the control group. Among RA patients surface expression of CD40-L was significantly higher in active RA patients compared to inactive patients. As regards CD40 expression on PB, no statistical significance was observed among the studied groups. Therefore increased expression of CD40-L on PB T-lymphocytes could be regarded as a marker of disease activity in RA patients and to drive the activation of autoreactive beta-lymphocytes in the disease. These findings are particularly useful for clarifying the pathogenic process in RA patients and for developing a therapeutic approach that blocks pathogenic cytokine and antibody production

Study of serum zinc, copper, magnesium, postassium and selenium in relation to serum Autoantibodies in siblings of type 1 diabetics

Aim: This work was intended to study the state of some elements namely zinc, copper, magnesium, potassium and selenium in sera of siblings of type 1 diabetic patients and its possible relation to some immunological markers. Subjects and The study included 208 subjects classified into 2 groups: group I included 108 siblings of type 1 diabetic patients and group II included 100 control subjects matched for age and sex. All subjects were subjected to the following: estimation of fasting and 2 hour postprandial plasma glucose and oral glucose tolerance test when needed. Determination of serum level of zinc, copper, magnesium, potassium and selenium was done using atomic absorption spectrophotometry. Measurement of serum insulin autoantibodies [IAA], antibodies to the protein tyrosine phosphatase-like proteins ICA512 [IA-2] and glutamic acid decarboxylase antibodies [GADA] was performed using radioimmunoassay [RIA] technique. The mean serum levels of zinc and copper were significantly higher [P = 0.000 for each], and the mean serum levels of selenium and potassium were significantly lower [P = 0.002 and 0.007, respectively] in type 1 diabetic siblings when compared with control subjects. Zinc and copper were significantly higher [P = 0.000 for each], and magnesium was significantly lower [P = 0.001] in the sera of siblings positive for IAA as compared to the seronegative cases. Selenium was found to be significantly lower in the sera of siblings positive for IAA, IA2 and GADA when compared to the seronegative cases [P = 0.000 for each]. Our results point to a disturbance in the serum levels of zinc, copper, selenium, potassium and magnesium. These nutritional elements may contribute as an environmental factor, that in conjunction with genetic factors, triggers the immunopathogenic sequence responsible, preceding and/or associated with beta cell damage in type 1 diabetes or its complications

GAD, IA-2 and insulin autoantibodies in relation to some risk factors in siblings of Egyptian children with type 1 diabetes

The aim of the present work has been to screen siblings of children with type 1 diabetes for some immunological markers of the disease, namely GAD, IA-2 and insulin autoantibodies and to study their possible relation with other risk factors. Siblings of 151 child with type 1 diabetes [287 healthy siblings] besides 100 healthy control subjects matched for age and sex. Subjects were subjected to estimation of GAD antibodies using radiolig and binding assay developed by Peterson et al, in 1994, IA-2 antibodies by radiolig and assay and insulin autoantibodies [IAA] using ELISA technique. Subjects with positive immunological markers were screened for HLA-DR3 and DR4 and first phase insulin release [FPIR] arter IV glucose infusion. revealed that 39.7% of healthy siblings were positive for one or more autoantibodies, 22.8% for 2 antibodies and 4.38% for 3 antibodies. GAD antibodies were present in 27.9%, IA-2 antibodies in 9% and IAA in 15.3% of healthy siblings. These prevalences were statistically significantly higher than those found in control subjects: 7%, 2%, 1.5% respectively No relation could be elicited between positivity of immunological markers in siblings and their age, sex, duration of breast feeding, age at cow's milk feeding nor with parents consanguinity. On the other h and, HLA-DR3, HLA-DR4 and DR3/DR4 were found in 29.4%, 64.7% and 88.2% respectively in seropositive subjects while in 27.5% 32.5% and 45% in seronegative healthy siblings. Conclusion the high prevalence of positivity of autoantibodies among siblings of type 1 diabetic children suggests the importance of an environmental factor, perhaps via a mechanism of antigenic mimicry. Also the results in relation to other risk factors may help to a better underst and ing of the immuno-genetic susceptibility and /or pathogenesis of type 1 diabetes in a particular population

Association of helicobacter pylori infection with cardiovascular disease in type 2 diabetic patients

This work was intended to study the possible association of H. pylori infection with cardiovascular disease in type 2 diabetic patients. The study included 180 subjects classified into four groups: Group I included 75 patients with both type 2 diabetes and CHD, Group II included 50 patients with type 2 diabetes, Group III included 30 patients with CHD and Group IV included 25 matched controls. All patients and controls were subjected to the following: complete history taking, thorough clinical examination and routine laboratory tests. Assessment of CHD was done by 12-lead resting electrocardiogram. H. pylori seiological status was assessed by ELISA which has a sensitivity and specificity of >/= 95%. Measurement of acute phase reactants [fibrinogen, CRP] and serum lipid profile was done. Testing for microalbuminuria was performed using micral test. H. pylori seropositivity was significantly higher both in patients with CHD [X[2] =14.97, p < 0.05], and in those with type 2 diabetes [X[2] = 6.89, p < 0.05] than in normal controls. Furthermore, H. pylori seropositivity was higher in diabetic patients with CHD than in diabetic patients without CHD [X[2]= 9.23, p< 0.05]. H. pylori seropositive subjects had significantly lower HDL-C level [t = 3.21, p < 0.05] and significantly higher plasma fibrinogen level [t = 2.76, p < 0.05] than the seronegative ones. No significant relation was found between H. pylori seropositivity and the duration of diabetes [t = 0.11, p > 0.05], fasting plasma glucose [t = 0.86, p > 0.05] or the presence of microalbuminuria [X[2]=0.74, p> 0.05]. Our results suggest that type 2 diabetes and CHD may be associated with H. pylori infection This association may be complicated by plasma fibrinogen level and /or modified serum lipid profile. In type 2 diabetic patients, the frequency of H. pylori infection is higher than in non-diabetic subjects. This could be related to the reduced gastric motility, glycosylation process in the gastric mucosa and diminished mucosal defense mechanisms

Apoptosis and endotoxins-induced secretion of interleukin-1B and tumor necrosis factor O by mononuclear cells in patients with acute versus chronic renal failure

Previous reports suggested a protective effect of chronic renal failure [CRF] against sepsis and endotoxin-induced organ failure and mortality in ARF. The present study was undertaken to investigate apoptosis and endotoxin-induced total production and secretion of interleukin-IB [IL-1B] and secretion of tumor necrosis factor a [TNF alpha] by mononuclear cells in patients with acute versus chronic renal failure. Lipopolysaccharide [LPS] induced IL-1B total production and secretion and TNF alpha secretion by peripheral blood mononuclear cells [PBMC] cultured for 18 hours were determined in patients with advanced CRF but not yet on dialysis [n=13], ARF patients [n=10] and healthy controls [n=10]. In vitro spontaneous apoptosis of cultured PBMC [for 18 hours] was also determined in these subjects. Suppressed secretion of IL-1B [629 +/- 490 pg/ml] by LPS stimulated PBMS was found in patients with CRF compared to patients with ARF [1989 +/- 1209 pg/ml, P<0.05] and healthy controls [1543 +/- 107.3 pg/ml, P<0.05]. A decrease in the total [1346 +/- 998.6 pg/ml] and cell associated [717 +/- 534 pg/ml] LPS induced IL-IB production was also found in them compared to those with ARF [39005 +/- 2516 pg/ml, P<0.05 and 1917 +/- 1308 pg/ml, P<0.05 for total and cell associated levels respectively]. Total production and secretion [absolute value] of LPS induced IL-1B were similar in patients with ARF and healthy controls but with increased cell associated IL-1B production in patients with ARF [P<0.05] LPS-induced TNF alpha secretion by PBMC did not differ significantly in the three groups. Accelerated spontaneous apoptosis of PBMC was found in patients with CRF [30.6 +/- 6.2%] compared to healthy controls [15.8 +/- 9.9%, P<0.05] and to patients with ARF [16.4 +/- 4.7%, P<0.05]. Negative correlation was found between% apoptosis of PBMC and secretion of both LPS induced IL-1B [P<0.01] and TNF alpha [P<0.01] by PBMC in patients with CRF. The reduced capability of PBMC from patients with CRF to secrete adequate amounts of IL-1B in response to LPS together with the accelerated spontaneous apoptosis may be protective mechanisms that decrease the deleterious effect of tissue necrosis and may partly explain the reported fair prognosis of ARF and sepsis in cases with prior CRF

Anti-atherogenic effect of circylating immune complexes in schistosomal hepatic fibrosis

This study included 29 normal control subjects and 76 SHF patients [33 with portosystemic collaterals, 12 with portosystemic collaterals and atherosclerosis, 18 without collaterals and 13 without collaterals with atherosclerosis]. Precipitation of circulating immune complexes [CICs] by ammonium sulfate at 25% saturation and estimation by nephelometry of CICs fractions; namely, immunoglobulins IgG, IgA, IgM, complement C3, apolipoproteins apoA and apoB were done for each subject. Patients with collaterals showed the highest levels of CICs, the atherosclerotic SHF without collaterals showed the lowest level. A similar pattern was shown for the total contents of IgG, IgA, IgM, apoxe A and B fractions of their CICs. Contrarily was the C3 fraction of the CICs which was generally low in the SHF Groups, except in the atherosclerotic group without collaterals who showed an astonishingly high level explaining the ability of their CICs to elicit immune endothelial injury