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PubMed2000

Autoimmune responses against oxidant stress and acetaldehyde-derived epitopes in human alcohol consumers.

BACKGROUND: Studies in experimental animals have indicated that chronic ethanol ingestion triggers the formation of antibodies directed against proteins modified with reactive metabolites of ethanol and products of lipid peroxidation. However, the nature and prevalence of such antibodies have not been compared previously in alcoholic patients. METHODS: Autoantibodies against adducts with acetaldehyde- (AA), malondialdehyde- (MDA), and oxidized epitopes (Ox) were examined from sera of 54 alcohol consumers with (n = 28) or without (n = 26) liver disease, and from 20 nondrinking controls. RESULTS: Anti-AA-adduct IgA and IgG antibodies were elevated in 64% and 31% of patients with biopsy-proven alcoholic liver disease (ALD, n = 28), respectively. The IgA titers were significantly higher than those from nondrinking controls (p < 0.001), or heavy drinkers without significant liver disease (p < 0.001). Anti-MDA adduct titers (IgG) were elevated in 70% of the ALD patients. These titers were significantly higher (p < 0.001) than those from nondrinking controls, or heavy drinkers without liver disease. Antibodies (IgG) against Ox epitopes occurred in 43% of ALD patients, and the titers also were significantly higher (p < 0.05) than those from nondrinking controls. The anti-AA and anti-MDA adduct titers in ALD patients correlated significantly with the combined clinical and laboratory index (CCLI) of liver disease severity (r(s) = 0.449, p < 0.05; r(s) = 0.566, p < 0.01, respectively), the highest prevalences of anti-AA-adducts (73%) and anti-MDA-adducts (76%) occurring in ALD patients with cirrhosis. CONCLUSIONS: The present results indicated that autoantibodies against several distinct types of protein modifications are generated in ALD patients showing an association with the severity of liver disease.

Acetaldehyde↗
PubMed2003

Characterization of the human autoimmune response to the major C-terminal epitope of the ribosomal P proteins.

Autoantibodies to the ribosomal phospho (-P) proteins P0, P1, and P2, collectively referred to as Rib-P, are specifically found in 10-40% of patients with systemic lupus erythematosus (SLE). These antibodies are believed to be correlated with lupus nephritis, hepatitis, and central nervous system involvement. The major immunoreactive epitope of these ribosomal antigens has been localized to the carboxy terminus, which is a highly conserved domain of all three proteins and contains two phosphorylated serine residues. The phosphorylated amino acids of the P proteins are known not to be critical epitope determinants. Furthermore, epitope-mapping studies have shown that the major epitope is located within the last 11 C-terminal amino acids. Using peptide arrays we identified more precisely this shared epitope as the six C-terminal amino acids GFGLFD and elucidated the molecular recognition events of anti-Rib-P antibodies at the amino acid level. We identified Phe(111) and Phe(114) of Rib-P2 as the key residues for the interaction, with further contributions of Gly-112 and Asp-115. This amino acid stretch is also present in proteins of several pathogenic micro-organisms such as Trypanosoma cruzi, Brugia malayi, Pseudomonas aeruginosa, Candida albicans, several Leishmania species, and Bartonella henselae. Using newly developed ELISA systems with a C-terminal peptide (C22) and the recombinant proteins (P0, P1, and P2) as antigens we found a high specificity of anti-Rib-P antibodies for SLE and demonstrated positive correlations with anti-U1-C, anti-Sm-B/B' and anti-D and anti-dsDNA antibodies. The sensitivity and specificity in the peptide (C22) based assay varied between 12.8%/100% and 23.4%/96.7% for SLE, depending on the assigned cutoff. In contrast to other studies, we found no significant correlation of anti-Rib-P reactivity with central nervous system manifestations or renal involvement in SLE patients. We conclude that the epitope motif GFGLFD in the C-termini of the ribosomal P proteins is the key determinant of anti-Rib-P antibodies, and that the C22 peptide and the recombinant proteins can be used equally well for the detection of anti-Rib-P antibodies. The role of the major Rib-P epitope in the development of anti-ribosomal P antibodies and in the pathogenesis of SLE remains a subject of further investigation.

Amino Acid Sequence↗
PubMed1996

Corneal infection with herpes simplex virus type 1 leads to autoimmune responses in rats.

Lewis rats were infected by corneal scarification with HSV type 1 type strain F virus. The animals showed symptoms of infection and inflammatory infiltrates of the eye but little mortality. After one month, immune responses to viral and autoantigens were examined. It was shown that lymph node cells proliferated to the myelin antigen, proteolipoprotein, and the HSV antigen, glycoprotein D, but showed depressed responses to antigens of the eye, specifically corneal and retinal antigens. Splenic cells showed small but significant responses to antigens of the eye, indicating immune deviation similar to that previously demonstrated in ACAID, where antigen had been injected into the anterior chamber of the eye.

Animals↗
PubMed2003

Regulation of viral and autoimmune responses.

We have studied the induction and effector function of Th2-like regulatory cells in mouse models for type 1 diabetes (NOD and RIP-LCMV). CD4+ lymphocytes with specificity for insulin can be induced by immunization with the insulin B chain via the oral route or by DNA vaccination. Such cells are protective upon adoptive transfer and prevent diabetes development in syngeneic pre-diabetic recipients. In comparison to non-regulatory insulin B-specific cell lines, they produce high amounts of interleukin (IL)4 and IL10, whereas interferon (IFN)gamma and tumour necrosis factor (TNF)alpha levels are comparable. Indeed, IL4 is essential for the protective capability, as evidenced by use of IL4-deficient mice and sorting of IL4+ versus IL4- lymphocytes prior to transfer. Mechanistically, these cells act as bystander suppressors in the pancreatic draining node, the location where their cognate antigen, insulin B, is presented during the pre-diabetic inflammatory process. As a consequence, the autoaggressive response is locally dampened. We propose that this is achieved by modulation of antigen presenting cells that lose the ability to propagate aggressive responses after exposure to IL4 or IL10 in vitro. The clinically attractive side of our strategy is that it only acts as the site of inflammation, thus circumventing systemic side effects. In order to avoid induction of insulin B-specific autoaggressive T cells we have demonstrated that administration of IL4 or IL10 at the time of immunization is beneficial and therefore should be part of a potential future clinical application. Interestingly, these Th2-like regulators share in our systems no features with the so-called CD25+ regulatory cells, whose antigen specificity is still unclear. However, we have recent evidence that virus specific CD25+ cells can be generated and are able to affect antiviral responses in vivo.

Animals↗
PubMed2003

In primary Sjögren's syndrome, HLA class II is associated exclusively with autoantibody production and spreading of the autoimmune response.

OBJECTIVE: To reevaluate, in a large series of patients with Sjögren's syndrome (SS) recruited from 2 French centers, the question of whether HLA is associated with SS itself or with a pattern of secretion of autoantibodies. METHODS: One hundred forty-nine white patients fulfilling the American-European Consensus Group criteria for SS were divided into 3 subgroups, according to their anti-Ro/SSA and anti-La/SSB status, as follows: group 1 (n = 53), no antibody; group 2 (n = 46), anti-SSA only; group 3 (n = 50), both anti-SSA and anti-SSB. Patients were compared with 222 unrelated healthy subjects representative of the white population in France. RESULTS: Comparisons between the 149 SS patients and 222 controls confirmed the association of SS with DRB1*03 (the frequency was 25% in patients versus 10% in controls) and DQB1*02 (32% versus 22%). The association between HLA and SS was restricted to patients with anti-SSA and/or anti-SSB; no association with HLA was observed in patients in group 1 (no antibody). The frequency of HLA-DRB1*15 was highest in group 2 (24%), compared with 11% in group 1 and 11% in controls, whereas the frequency of HLA-DRB1*03 was highest in group 3 (44%), compared with 12% in group 1, 19% in group 2, and 10% in controls. Group 2 and group 3 had more clinical and biologic markers of activity than did group 1 but were not clinically different. HLA alleles were not associated with clinical features of the disease, and were associated with only some biologic features: rheumatoid factor positivity, increased serum IgG, and thrombocytopenia were associated with HLA-DRB1*03, and neutropenia was associated with DQB1*01. CONCLUSION: HLA class II markers confer genetic susceptibility to Sjögren's syndrome. The association between HLA and SS is restricted to patients with anti-SSA and/or anti-SSB antibodies; HLA is not associated with SS in patients without these autoantibodies. The absence of a difference in disease severity between groups 2 and 3, as well as the restricted association of HLA-DRB1*03 in group 3, strongly suggest that HLA alleles predispose to autoantibody secretion, without being associated with clinical outcome. HLA class II phenotype might support epitope spreading: HLA-DR15 favors anti-SSA synthesis, whereas HLA-DR3 is associated with both anti-SSA and anti-SSB production.

Adult↗
PubMed1991

Acute familial myositis with a common autoimmune response.

In 1986, we diagnosed and treated 4 patients, all members of 1 rural family, who presented simultaneously with a polymyositis-like syndrome, anticytoplasmic antibodies (on HEp-2 cells), and precipitating antibodies of anti-Jo-1 and anti-PM-Scl specificities. Serum samples from these patients reacted by immunodiffusion against serum from a rodent that had been caught in the patients' house. The precipitin line showed complete immunologic identity with anti-Jo-1. To study the specificity of this serum-serum reaction, 2 mice (Mus musculus) and 1 rat (Rattus rattus) from the neighboring areas of the patients' house were caught and killed. Sections of the liver, kidney, spleen, and skeletal muscle were processed for histopathologic examination and for direct and indirect immunofluorescence studies of the patients' sera. The rodents' sera were tested by immunodiffusion against serum samples from 25 patients with systemic lupus erythematosus, 11 with rheumatoid arthritis, 6 with mixed connective tissue disease, and 11 with various other rheumatic diseases, as well as 16 healthy controls. A serum-serum precipitin reaction was noted between the rodents' sera and sera from 2 of the patients with polymyositis-like syndrome. A distinct, but weaker, reaction was found with 2 lupus patients' sera (8%), and with 1 healthy control serum (6%). The rodents' sera were antinuclear antibody positive by indirect immunofluorescence on HEp-2 cells. These results, suggest that some rodents could be carriers of an as-yet-unknown transmissible agent that, in susceptible individuals, induces clinical and serologic manifestations similar to those of polymyositis.

Acute Disease↗
PubMed1989

Establishment of an anti-A human monoclonal antibody from a blood group A lung cancer patient: evidence for the occurrence of autoimmune response to difucosylated type-2 chain A.

A human monoclonal antibody, NCC-HAL-27, has been established by a combination of transformation by Epstein-Barr virus (EBV) and a newly devised "micro cell fusion" technique. Lymphocytes used were derived from a blood group A lung cancer patient. Cancer cells, as well as normal epithelial cells of lung, stomach and colon (including autologous tissue) from blood group A individuals, fixed in formalin, were immunohistochemically stained by the antibody. A higher concentration (greater than 140 mg/ml) of the antibody agglutinated only type-A (not B or 0) erythrocytes. The structural specificity of NCC-HAL-27 was determined by particle-concentrated fluorescence immunoassay and thin-layer chromatography immunostaining using purified, well-defined glycolipids. The antibody was found to be directed against type-2 chain A and difucosylated type-2 chain A antigens with no cross-reactivity with known A-like antigens, such as Tn and Forssman antigen, generally expressed irrespective of ABO status. Interestingly, however, the antibody detected the expression of incompatible A antigen in colon cancers of B and 0 individuals with high incidence (30%-40%). The finding that a monoclonal antibody generated from a blood group A cancer-bearing host is directed against autologous A antigen is novel because the ABO blood group antigens are the major alloantigens in man, with strictly controlled immunotolerance. The induction of anti-A in this patient could, therefore, be directly associated with the lung cancer.

ABO Blood-Group System↗
PubMed1983

Lung cancer patients' autoimmune responses to Thomsen-Friedenreich (T) antigen: diagnostic utility.

The usefulness of T antigen in the diagnosis of lung cancer (LCA), including early, was assessed by determining the in vitro delayed type hypersensitivity response to T(DTHR-T), and by measuring with a solid phase immunofluorescent assay the serum anti-T IgM response. Sensitivity of DTHR-T was 89% for 73 patients with LCA including 8/9 with Stage T1N0M0 disease, overall specificity was 95% for 212 healthy persons and those with non-CA disease. The humoral immune assay detected 31/35 (89%) LCA patients including 4/5 Stage T1N0M0 patients. Overall specificity was greater than 90% among 116 persons without CA.

Antibody Formation↗
PubMed1983

The effect of cyclophosphamide on autoimmune response to rats immunized with modified accessory glands.

It was found that the organ specific hemagglutinating autoantibodies to rat male accessory glands can be suppressed by the injection of a single dose of cyclophosphamide applied 3 days after the first immunization. On the other hand, injection of the drug 3 days before immunization did not modify the response, that is, there were comparable incidence and titers in both treated and the control animals. Cyclophosphamide did not appear to act on the homocytotropic antibodies. These results indicate that cyclophosphamide acts only when it is administered after antigenic stimulation, to suppress hemagglutinating antibodies production.

Animals↗
PubMed1994

Polyreactive autoimmune response induced by PC 12 cell grafts into rat striatum.

In order to better characterize the autoantibodies induced by PC12 cells grafted into rat brain, we have tested sera from these animals by immunoblotting with several preparations, including phosphorylated and dephosphorylated neurofilaments, keratins, PC12 cells and proteins from various rat tissues, and by immunofluorescence of rat spinal cord neurons in culture. Sera from grafted rats reacted with several antigens present in all tissues tested and stained in cultured neurons not only NF but also cell bodies and membranous granular structures. These observations suggest either the polyreactivity of autoantibodies or the induction of a polyclonal B cell activation consecutive to the release of central nervous system antigens into the blood stream. These results are discussed with regard to the role of NF autoantibodies in neurodegenerative diseases.

Animals↗