Immune complex mediated vasculitis in hepatitis b and c infections and the effect of antiviral therapy

Case reports of seven patients with vasculitis and past or present viral hepatitis infection are presented, including studies on circulating immune complexes (CICs) and cryoglobulins by sucrose density gradient centrifugation or gel filtration, before and after antiviral therapy. Three patients had unusual vasculitic manifestations: coronary, large vessel, and muscle vasculitis, respectively. All the patients had high levels of CICs by the above methods, but only two had CICs by the C1q binding and conglutinin methods. The CICs/cryoglobulins contained HBV and/or HCV antibodies, antigens, and genome. The concentration of hepatitis antibodies in immune complex form was severalfold higher than in the free form in serum. In one patient, the HBs antigen was present only in the CICs and in another, only hepatitis antibodies (no antigen/genome) were present in the serum or the cryoglobulins. With antiviral therapy, six patients went into longlasting remissions. There was a temporal relationship between the regression of the vasculitic lesions and the decline in the levels of CICs/cryoglobulins

LDL immunization induces T-cell-dependent antibody formation and protection against atherosclerosis

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Polymorphisms in the IL-10 but not in the IL-1{beta} and IL-4 genes are associated with inhibitor development in patients with hemophilia A.

The aim of the Malmö International Brother Study (MIBS) is to evaluate host genetic factors associated with the development of inhibitory antibodies in patients with hemophilia. Factor VIII gene mutations and genetic polymorphisms of the IL1beta, IL4, and 100 genes, known to influence antibody production in autoimmune diseases, were analyzed in 164 patients (124 with severe, 26 with moderate, and 14 with mild disease) in 78 unrelated families with hemophilia A. Seventy-seven (47%) patients in 54 families had a history of inhibitors (57 high responding, 20 low responding). Inversions were found in 36 families (75 patients). There was no association between the development of inhibitor and the IL1beta Taql RFLP alleles in exon 5 or the -590 C/T single nucleotide polymorphism (SNP) in the promoter region of IL4. There was, however, a strong association between an allele with 134 bp in one of the CA repeat microsatellites, IL10G, located in the promoter region of the IL10 gene, and the development of inhibitor (odds ratio [OR], 4.4; 95% confidence interval [95% CI], 2.1-9.5; P < .001). The association was consistent in the subgroup of families with severe hemophilia and inversions. IL10 is the first gene located outside the causative factor VIII gene mutation to be associated with inhibitor development

Circulating immune complexes in 50-year old men as a strong and independent risk factor for myocardial infarction

Background: Circulating immune complexes (CICs) and autoantibodies against oxidatively modified LDLs (oxLDLs) and cardiolipin occur in patients with atherosclerosis and myocardial infarction (MI). The ability of such CICs and antibodies to predict myocardial infarction (MI) was investigated in a prospective nested case-control study in which healthy 50-year-old men were followed for 20 years. Methods and Results: Two hundred fifty-seven men were included in the study, and 119 developed MI (39 died) between 50 and 70 years of age. One hundred thirty-eight randomly chosen men who did not develop MI up to 70 years of age served as controls. The prevalence of elevated levels of CICs and the concentration of CICs in men who developed MI were higher than in those who remained healthy. The concentration of CICs at age 50 was associated with a marked increased risk for MI, and this risk was independent of other conventionally recognized risk factors. There was a positive correlation between the levels of CIC and IgG antibodies to cardiolipin in men who developed MI. The level of IgG antibodies and the prevalence of elevated IgG and IgM antibodies to cardiolipin were higher in those who developed MI and had CICs than in those without CICs. Among men homozygous for C4 null alleles, those who developed MI had higher concentrations of CICs than did those who remained healthy. Conclusions: This prospective study shows that CICs alone or in combination with autoantibodies against cardiolipin in healthy males at 50 years of age predict subsequent MI between the age of and 70 years

Antibodies against cardiolipin and oxidatively modified LDL in 50-year old men predict myocardial infarction

Autoantibodies against oxidatively modified low-density lipoproteins (oxLDL) and cardiolipin occur in patients with vascular diseases, including atherosclerosis. The ability of such antibodies to predict myocardial infarction (MI) was investigated in a prospective nested case-control study in which healthy 50-year-old men were followed up for 20 years. Raised levels of antibodies against oxLDL and cardiolipin at 50 years of age correlated positively with the incidence of MI and mortality related to MI 10 to 20 years later. IgG and IgA antibodies against cardiolipin were associated with MI between 50 to 60 years of age and IgG and IgA antibodies against oxLDL with MI at 60 to 70 years of age. Moreover, higher antibody levels were noted in those who died from acute MI in comparison to those who survived. The predictive power of IgA and IgG antibodies was strong and largely independent of that of other strong risk factors. In conclusion, raised levels of antibodies against oxLDL and cardiolipin may predict MI and MI-related death

Polymorphisms in the TNFA gene and the risk of inhibitor development in patients with hemophilia A.

The HLA class I/II alleles and the tumor necrosis factor alpha (TNFA) locus are closely linked in the MHC complex. We have characterized the causative factor VIII mutation, HLA alleles as well as 4 polymorphisms (-827C > T, -308G > A, -238A > G, and 670A > G) in the TNFA gene in 164 patients (124 severe, 26 moderate, and 14 mild) in 78 families with hemophilia A enrolled in the Malmo International Brother Study (MIBS). Inhibitors were identified in 77.8% of patients with a single haplotype (Hap 2) and 72.7% of the patients with the TNFA -308 A/A genotype within this haplotype compared with 39.70/6 for TNFA -308 G/G patients and 46.9% for TNFA -308 G/A heterozygotes (OR 4.0; 95% CI, 1.4-11.5; P = .008). The association between the -308 A/A genotype and inhibitors was enhanced in subgroups of patients with severe hemophilia (OR 19.2; 95% CI 2.4-156.5; P A polymorphism within Hap 2 is a useful marker and potential modulator of the immune response to replacement therapy in patients with hemophilia

T cell expansions with conserved T-cell receptor β chain motifs in the peripheral blood of HLA-DRB1*0401 positive patients with necrotizing vasculitis

T lymphocytes are implicated in the pathogenesis of systemic vasculitis such as Wegener's granulomatosis (WG) and polyarteritis nodosa (PAN). In the present study, we have characterized in detail the T-cell receptor (TCR) of peripheral blood T cells from eight vasculitis patients of known HLA class II genotypes. We used flow cytometry to outline the exact TCR V gene expression, complementarity determining region 3 (CDR3) fragment analysis to estimate the degree of clonality and cDNA sequencing to define the exact TCR ∓ or β chain sequences. The TCR CDR3 region interacts with antigenic peptides presented by HLA molecules, and it is normally immensely diverse. It was therefore of particular interest to identify a common dominating TCR BV8-F/L-G-G-A/Q-G-J2S3 β chain sequence in the CD4+T cells of four unrelated vasculitis patients. Furthermore, this BV8-associated CDR3 motif was linked to the HLA-DRB1*0401 allele, as well as to active disease and/or an established BV8+ CD4+ T-cell expansion. In contrast, age- and HLA-matched patients with rheumatoid arthritis did not harbor the described BV8 motif. These results strongly suggest that BV8+ CD4+ T cells with the described CDR3 motif recognize a specific antigen presented by DR4 molecules, indicating the existence of a common vasculitis-associated antigen