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Objectives: Rheumatoid arthritis (RA) is a chronic disease characterised by a pro-inflammatory cytokines linked erosive joint damage and by humoral and cellular response against a broad range of self-peptides. Molecular mimicry between Epstein-Barr virus (EBV), Mycobacterium avium subsp. paratuberculosis (MAP) and host peptides has long been regarded as an RA pathogenetic mechanism. Using bioinformatic analysis we identified high sequence homology among interferon regulatory factor 5 (IRF5), EBV antigen BOLF1 and MAP antigen MAP&#95;4027. Our objective was to evaluate the presence in sera of RA patients of antibodies (Abs) directed against human homologous IRF5 cross-reacting with BOLF1 and MAP&#95;4027., Methods: Frequency of reactivity against IRF5424-434, BOLF1305-320 and MAP&#95;402718-32 was tested by indirect ELISA in sera from 71 RA patients and 60 healthy controls (HCs)., Results: RA sera show a remarkable high frequency of reactivity against IRF5424-434 in comparison to HCs (69% vs. 8%; p<0.0001). Similarly, seroreactivity against BOLF1305-320 was more frequently detected in RA sera than in HCs counterpart (58% vs. 8%; p<0.0001). Frequency of Abs against MAP&#95;402718-32 was 17% in RA sera vs. 5% in HCs with a p-value at the threshold level (p<0.051). Prevalence of Abs against at least one of the assessed epitopes reached 72% in RA patients and 15% among HCs. Levels of Abs in RA patients were significantly related to systemic inflammation., Conclusions: IRF5 is a potential autoimmune target of RA. Our results support the hypothesis that EBV and MAP infections may be involved in the pathogenesis of RA, igniting a secondary immune response that cross-reacts against RA self-peptides.

Our objective was to determine the HLA-DPB1 allele associations of anticardiolipin (aCL) and anti-beta2GPI (a(beta)2GPI) antibodies, and of clinical manifestations of the antiphospholipid syndrome (APS), in systemic lupus erythematosus (SLE). We studied 577 European patients with SLE. aCL and a(beta)2GPI antibodies were measured by ELISA. Molecular typing of HLA-DPB1 locus was performed by polymerase chain reaction-sequence specific oligonucleotide probe (PCR-SSOP) method. aCL showed positive association with -DPB1*1501 (P = 0.005, OR = 7.4), and -DPB1*2301 (P = 0.009, OR = 3.3). a(beta)2GPI showed positive association with -DPB1*0301 (P = 0.01, OR = 1.9), and -DPB1*1901 (P = 0.004, OR = 8.1). In addition, livedo reticularis was associated with -DPB1*1401, and Raynaud's phenomenon with -DPB1*2001. In conclusion, HLA-DPB1 locus may contribute to the genetic predisposition to develop antiphospholipid antibodies and clinical manifestations of the APS in patients with SLE.

Objective: To assay anti-ganglioside antibodies (aGM1) in sera of a large cohort of European patients with systemic lupus erythematosus (SLE) to define the prevalence of these autoantibodies in SLE; to evaluate the association of aGM1 with clinical manifestations and other autoantibodies found in SLE; and to search for aGM1 association with HLA class II alleles., Methods: Four hundred forty-eight patients with SLE were consecutively enrolled in 8 centers from 6 European countries. All sera were tested for antinuclear antibodies by immunofluorescence on HEp-2 cells as substrate, anti-dsDNA, aGM1, aCL, abeta2-glycoprotein I (abeta2-GPI) antibodies by ELISA, and antineutrophil cytoplasmic antibodies (ANCA) by immunofluorescence and by ELISA. Genomic typing for HLA class II loci was performed by polymerase chain reaction-sequence specific oligonucleotide probe method. Clinical assessment was done at the time of enrolment., Results: We found 41.9% of patients with clinical signs of neuropsychiatric involvement; 15.5% of patients were positive for aGM1, 8% of the IgG isotype and 8.6% of the IgM isotype; aGM1-IgG were associated with neuropsychiatric manifestations (NPM) (RR = 3.7), with migraine (RR = 2.4), with OBS (RR = 7.3), and with peripheral neuropathy (RR = 8.5). aGM1-IgM were associated with NPM (RR = 4) and with depression (RR = 3.4). Furthermore, the genetic study showed that aGM1-IgG were associated with HLA-DQB1*0404 (RR = 7.2) while aGM1-IgM were associated with HLA-DQB1*0605 (RR = 33.3). No associations were found between aGM1 and anti-dsDNA, aCL, abeta2GP1, or ANCA., Conclusion: Our results show aGM1 can be found in patients with SLE. aGM1 may play a pathogenetic role for some NPM in this condition.

In order to ascertain whether the HLA-DP locus plays a role in the genetic predisposition for systemic lupus erythematosus (SLE), 42 patients with SLE were typed for 17 different DPBeta haplotypes by locus specific amplification followed by allele specific oligonucleotide hybridization. Sera from the same patients were assayed for the presence of autoantibodies to Sm, RNP, Ro, La and of anticardiolipin antibodies (aCL). DPB1*0301 and DPB1*1401 were increased in patients compared with 107 healthy controls, mainly in those anti-Sm/RNP positive and aCL positive. Remarkably, DPB1*1401 and DPB1*0301 have a nearly identical nucleotide sequence, suggesting that an epitope shared by their membrane products is of major importance for the DP related susceptibility to SLE.

Antiphospholipid antibodies (aPL) have been linked to various clinical manifestations in systemic lupus erythematosus (SLE), mainly thrombosis, repeated abortions and thrombocytopenia. Despite the large number of studies which have been published in the recent years, there is still some debate on this matter, and no firm conclusion has been reached as yet. Among the various aPL, anticardiolipin antibodies (aCL) have received more attention, mostly because they can be easily detected by means of immunoenzymatic assays. The main objective of the present study was to determine the prevalence of IgG and IgM aCL isotypes in SLE in order to compare their possible association with the clinical manifestations of the disease. Clinical features of 40 consecutive and unselected SLE patients (35 female and 5 male) were prospectively studied. Sera from the same patients were tested for the presence of aCL, using a standardised ELISA assay, and the presence of aCL was correlated with the various clinical events. Results showed that the prevalence of aCL was 42.5% for the IgG isotype and 10% for the IgM isotype. Regarding the clinical associations of aCL, we found a strong linkage between the presence of these antibodies and the occurrence of both thrombosis and abortions; a weaker association with neurological events was also demonstrated. These results, if confirmed on larger series, suggest that aCL should be searched in patients with SLE in order to identify those who are at greater risk of developing some severe clinical problems and could benefit by prophylactic treatment.

The aim of this study was to evaluate morphological and functional abnormalities by cerebral imaging in a series of systemic lupus erythematosus (SLE) patients with and without overt central nervous system (CNS) manifestations, and to detect possible relationships with clinical parameters and a large panel of autoantibodies, including those reactive against neurotypic and gliotypic antigens. 68 patients with SLE were investigated in a cross-sectional study which included clinical evaluation of symptoms, cerebral magnetic resonance imaging (MRI) and brain single photon emission tomography (SPECT) analysis, electroencephalography (EEG), and serological tests for antibodies directed against nuclear, cytoplasmic neuronal and glial cell-related antigens. The results of this study showed: (1) a significant positive association of (a) anti-glial fibrillary acidic protein (GFAP) serum antibodies with neuropsychiatric (NP) manifestations and (b) anti-serin proteinase 3 (anti-PR3/c-ANCA) serum antibodies with pathological cerebral SPECT; (2) the presence of significantly higher values of (a) SLICC organ damage index in patients with abnormal MRI and (b) SLAM activity index in patients with abnormal SPECT; and (3) the association of (a) abnormal MRI with nonactive NP manifestations and (b) combined abnormality of brain SPECT and MRI with the occurrence of overall overt NP manifestations and with those of the organic/major type. Neuropsychiatric manifestations, namely those of the organic/major type, appeared to be significantly associated to the presence of a serum antibody against GFAP, a gliotypic antigen. There was also evidence of an association between SPECT abnormality and the presence of anti-PR3 (c-ANCA). Furthermore, brain imaging by MRI and SPECT applied to SLE patients appears to express CNS involvement significantly related to specific categories of NP manifestations. The abnormalities detected by the two tests seem to be preferentially associated with different activity phases of the NP disorder or of the lupus disease. Lupus (2000) 9, 573–583. [ABSTRACT FROM AUTHOR]