Autoantibodies in healthy subjects of different age groups

Autoantibody determinations in 1284 healthy Caucasian subjects of various age groups were made by indirect immunofluorescence for anti-nuclear, anti-gastric, and anti-thyroglobulin antibodies. A sex-dependent relationship between age and prevalence of anti-gastric and anti-thyroglobulin antibodies was found. No association was found between age and anti-nuclear antibodies.     

Immunoglobulin allotypes and virus antibodies in Finnish type 1 diabetic patients

We have found elevated IgA class mumps and Coxsackie B4 virus antibodies and IgA/IgG antibody ratios in type 1 diabetic patients. However, IgA class herpes simplex (HSV1) virus antibodies showed no difference between patients and controls. To study the possible contribution of genetically polymorphic immunoglobulin markers to the pronounced IgA class reactivity Ig allotypes (Gm, A2m and Km determinants) were compared to virus antibodies in diabetic patients and healthy controls. Ig allotypes were equally distributed in both groups suggesting that the genes coding for these structures are not in close linkage disequilibrium with susceptibility gene(s) for type 1 diabetes. Accordingly, pronounced IgA class immune response in diabetic patients is hardly due to Ig allotype related factors. Patients had elevated IgA class mumps and Coxsackie B4 antibodies and IgA/IgG antibody ratios independently of the Gm phenotype group. In healthy subjects but not in diabetic patients IgA class mumps antibody levels and IgA/IgG mumps antibody ratios significantly correlated with the Gm phenotypes. Such Gm association was not observed in Coxsackie B4 or HSV1 antibodies. These results suggest that though Gm phenotypes have a general effect on mumps specific antibody response, some other factors than Ig allotypes are responsible for the elevated IgA class mumps and Coxsackie B antibody levels and IgA/IgG antibody ratios in type 1 diabetes.     

Autoantibodies in malaria, tuberculosis and hepatitis B in a west African population.

Following reports of associations between autoantibodies and living in the tropics, we have studied the seroprevalence and nature of anti-nuclear antibodies, anti-cardiolipin antibodies, antibodies to extractable nuclear antigens and anti-neutrophilic cytoplasmic antibodies in 351 West Africans with malaria, tuberculosis or hepatitis B, or in good health. Amongst healthy West Africans we found a seroprevalence of 7% for anti-nuclear antibodies with several staining patterns, and of 30.3% for anti-cardiolipin antibodies. Among patients with tuberculosis and malaria there was twice that frequency of anti-nuclear antibodies (predominantly speckled in pattern), and anti-neutrophil cytoplasmic antibodies (predominantly IgM) were demonstrated in a few cases. A possible association between IgG anti-cardiolipin antibodies and tuberculosis was observed (P < 0.05), but antibodies to double-stranded DNA were not elevated and no antibodies to extractable nuclear antigens were found in any of the patients or healthy individuals studied. Our findings suggest the need for caution in the interpretation of autoantibody tests in subjects from or living in the tropics, as well as in patients with tropical infections.     

A comprehensive evaluation of serum autoantibodies in primary biliary cirrhosis

In primary biliary cirrhosis (PBC) serum markers other than anti-mitochondrial antibodies (AMA) are promising in terms of disease severity and comorbidities, as well represented by anti-nuclear antibodies (ANA). The aim of the present study was thus to evaluate the prevalence and clinical significance of a large profile of serum autoantibodies in PBC sera. We utilized 69 sera from European patients with PBC (including 20 AMA-negative) and 297 sera from geographically and sex-matched healthy controls. All sera were tested for the presence of ANA and autoantibodies associated with thrombophilia, vasculitis, and gastrointestinal disease. Autoantibodies other than AMA were detected in 53/69 (76%) PBC sera vs. 105/297 (35%) among controls. The prevalence of ANA (targeting dsDNA, Sm, chromatin, ribosomal-P, RNP, SmRNP, SSA, SSB, and centromere) and thrombophilia-associated autoantibodies (i.e. anti-β2GPI, phosphatydilserine, prothrombin) was common among patients with PBC. When clinical features were compared, the presence of anti-prothrombin IgM was associated with a worse prognosis as represented by a higher Mayo score. We demonstrate an increased prevalence of ANA and thrombophilia-associated autoantibodies in PBC sera and an association between the latter autoantibodies and PBC stage. The role of thrombophilia-associated antibodies will warrant further studies, based in particular on the incidence of portal hypertension at early stages of PBC.     

HLA antigens and immunoglobulin allotypes in patients with malignant melanoma

HLA antigens and Gm, A2m, and Km allotypes were examined in Caucasian patients with malignant melanoma. No significant associations were found for any of the HLA antigens tested. Significant association was found with Gm(2), and the relative risk for individuals with this marker was calculated at 1.9. The data indicate that Caucasians positive for Gm(2) are almost twice as likely to develop malignant melanoma as those without this marker.     

Autoantibodies in sera of Thai patients with Plasmodium falciparum infection.

Serum from 98 Thai adults infected with Plasmodium falciparum were examined for the presence of autoantibodies. Malarial containing antibodies sera were also revealed positive for anti-nuclear antibodies with fluorescence speckled pattern, anti-smooth muscle antibodies, anti-mitochondria antibodies and rheumatoid factor. There was no detectable antibody to double stranded DNA. There was a significant relationship between high titre of malarial antibody and high frequency of speckled pattern of anti-nuclear factor or anti-nuclear antibodies. By the ELISA technique determination of serum antibodies against an extractable nuclear antigen (ENA) in patients with P. falciparum infection gave 43.8% (43 of 98) positive result. In addition, sera contained malarial antibodies gave positive antibodies to ENA in 50% (49 of 98) by tanned red cell haemagglutination. Among the positive sera with antibodies to ENA, they showed the presence of antibodies to both ribonucleoprotein RNAase sensitive (RNP) and ribonucleoprotein RNAase resistance (Sm). Also both of antibodies exhibited positive staining of speckled pattern of antinuclear factor. This observation indicated that malaria infection induces autoantibodies which were predominantly anti-nuclear antibodies.     

Parental segregation of autoimmunity in patients with Turner's syndrome: preferential paternal transmission?

The prevalence of autoantibodies has been reported to be increased in both patients with Turner's syndrome and their parents. We evaluated organ-specific and non-organ-specific autoantibodies in 95 patients, ranging in age from infancy to adulthood, and in most of their parents, in order to determine the characteristics of autoimmune disorders in these families and to relate it to the genetic markers usually involved in autoimmunity (HLA, GM and KM genes). A statistically significant difference was observed between Turner patients and controls in the frequencies of organ-specific autoantibodies, in particular thyroid microsomal antibodies and thyroglobulin antibodies; however, the presence of autoantibodies was not associated with overt diseases in most cases. No significant difference was found between parents and controls. A study of the inheritance of the autoimmunity showed that transmission was preferentially paternal, since Turner patients had more chance of presenting autoantibodies when their fathers had autoantibodies rather than their mothers. A positive association was found between the presence of auto-antibodies and HLA-DR7;DQ2 and HLA-DR7;DQ9 haplotypes in Turner patients and fathers. No significant association was found between GM and KM allotype frequencies in Turner patients and their parents and the presence of autoantibodies. No epistatic interaction was demonstrated between HLA and GM or KM genes. Familial segregation was studied and a preferentially paternal transmission of HLA-DR7-carrying haplotypes and possibly also of the KM (1) allotype with autoimmunity was observed.     

Prevalence of autoantibodies to the p53 protein in autoimmune hepatitis

The target antigens of anti-nuclear autoantibodies in autoimmune hepatitis (AIH) are poorly characterised. Since antibodies to the p53 nuclear protein have been reported in various autoimmune diseases, we have assessed the prevalence of these antibodies in patients with AIH (n = 45), primary biliary cirrhosis (n = 60), hepatitis B (n = 22), hepatitis C (n = 55), and in a control group of subjects with various non-liver diseases (n = 56). A significant proportion of patients with AIH (31%) had elevated levels of autoantibodies to the p53 protein. In contrast, the prevalence of these antibodies in primary biliary cirrhosis (8%) and viral hepatitis (6%) was similar to that in the control group (4%). The clinical features of the anti-p53 seropositive AIH patients were similar to those of the seronegative ones. Thus, the prevalence of p53 autoantibodies in AIH is higher than in other forms of chronic hepatitis, and may be useful in differential diagnosis.     

Immunoglobulin heavy chain allotypes in a sample of Sicilian patients with celiac disease

The authors have studied the immunoglobulin heavy chain allotypes in 14 Sicilian patients with celiac disease (CD) and in 75 healthy controls. No association has been found between CD and Gm or Km phenotypes. When the role of Gm phenotypes in immune response against gliadin was analyzed, fb-positive CD patients on gluten-free diet for 1 year showed an increased antigliadin IgG response. Comparing the values of fb-positive subjects with those of negative ones, a significant difference was observed. These data, demonstrating that the presence or absence of a phenotype is able to define the breadth of immune response against alpha-gliadin antigen, are indicative of the role played by Ig allotypes in CD.     

Autoantibodies to DFS70/LEDGF are increased in alopecia areata patients

Alopecia areata (AA) has been suspected to be an autoimmune disease, although there is no distinct evidence, we investigated the relationship between AA and autoantibodies against dense fine speckles 70 kDa (DFS70) in 111 patients with alopecia and 105 healthy controls. The sera from 59 out of 111 (53%) Japanese alopecia patients were positive for anti-nuclear antibody (ANA), as compared to the sera of 16 out of 105 (15%) healthy controls (p < 0.001). Twenty percent (22/111) of the alopecia patients were shown to be positive for the prevalence of anti-DFS70 antibodies, as compared to 8% (8/105) of the healthy controls (p < 0.01). IgG subclass analysis by ELISA showed that IgG1 and IgG2-anti-DFS70 antibodies were dominant in alopecia patients. The DFS70 gene expression in the hair structures was clearly detected in both those with and those without the anti-DFS70 antibody by RT-PCR. Immunohistochemical techniques showed that the DFS70 was localized predominantly in the outer root sheath (ORS) cells. The elevated anti-DFS70 antibodies in alopecia patients and the localization of the DFS70 in the ORS suggest that autoantibodies against the DFS70 are related to the etiology in a certain population of AA.     

Association between human IgM autoantibodies and kappa chain allotypes

The relationship between the immunoglobulin kappa light chain allotypes and autoantibodies was studied in a series of seven human monoclonal kappa-bearing IgM antibodies with Rheumatoid Factor (RF) activity, two IgM anti-low density lipoprotein (LDL) antibodies, and one IgM anti-intermediate filament (IF) antibody. Residues at amino acid positions 153 and 191 related to the Km allotypes in human kappa chains were determined by an HPLC tryptic fingerprint and corroborated by amino acid sequence analysis. All the autoantibodies shared similar variable regions derived from the V kappa IIIb gene(s). The seven RF and the anti-IF were associated with the Km(3) constant region allotype whereas the two anti-LDL were associated with the Km(1,2) allotype. Thus, monoclonal autoantibodies showed the same Km allotypic distribution as the normal population. However, although the number of samples is small, it seems likely that a preferential association may exist between particular V kappa genes and Km alleles in the generation of autoantibodies with different specificities.     

Murine lupus strains differentially model unique facets of human lupus serology

Systemic lupus erythematosus (SLE) is a polygenic autoimmune disease characterized by the production of anti-nuclear autoantibodies that lead to subsequent end organ damage. Previous array-based studies in patients with SLE have shown that high immunoglobulin (Ig)G anti-nuclear autoantibody reactivity was associated with severe renal lupus, whereas IgM polyreactivity was associated with less severe disease. To ascertain how different murine lupus strains recapitulate these different autoantibody profiles seen in patients, serum from New Zealand black (NZB)/NZ white (W) F(1), Murphy Roths large (MRL)/lpr, NZ mixed (M)2410 and BXSB strains were compared using a comprehensive array-based screen. The array results were verified using enzyme-linked immunosorbent assays (ELISAs). Serum from MRL/lpr mice exhibited high levels of IgG anti-nuclear antibodies as well as anti-glomerular antibodies and variable levels of antibodies to myosin, Matrigel and thyroglobulin. Elevated anti-nuclear IgG antibodies were associated with severe nephritis in this strain. In contrast, NZM2410 mice exhibited lower IgG autoantibody levels with less severe nephritis but a significantly higher polyreactive IgM autoantibody profile. ELISA analysis confirmed these results. The NZB/NZW F(1) and BXSB strains exhibited an intermediate serological profile. Hence, just as in patients with SLE, whereas strong IgG reactivity to nuclear antigens is associated with severe renal disease, a polyreactive IgM seroprofile is also less ominous in murine lupus.     

ASSOCIATION BETWEEN HUMAN IgM AUTOANTIBODIES AND κ CHAIN ALLOTYPES

The relationship between the immunoglobulin kappa light chain allotypes and autoantibodies was studied in a series of seven human monoclonal kappa-bearing IgM antibodies with Rheumatoid Factor (RF) activity, two IgM anti-low density lipoprotein (LDL) antibodies, and one IgM anti-intermediate filament (IF) antibody. Residues at amino acid positions 153 and 191 related to the Km allotypes in human kappa chains were determined by an HPLC tryptic fingerprint and corroborated by amino acid sequence analysis. All the autoantibodies shared similar variable regions derived from the V gene(s). The seven RF and the anti IF were associated with the Km(3) constant region allotype whereas the two antiLDL were associated with the Km(1,2) allotype. Thus, monoclonal autoantibodies showed the same Km allotypic distribution as the normal population. However, although the number of samples is small, it seems likely that a preferential association may exist between particular V, genes and Km alleles in the generation of autoantibodies with different specificities.     

Prevalence of Autoantibodies to the p53 Protein in Autoimmune Hepatitis

The target antigens of anti-nuclear autoantibodies in autoimmune hepatitis (AIH) are poorly characterised. Since antibodies to the p53 nuclear protein have been reported in various autoimmune diseases, we have assessed the prevalence of these antibodies in patients with AIH (n = 45), primary biliary cirrhosis (n = 60), hepatitis B (n = 22), hepatitis C (n = 55), and in a control group of subjects with various non-liver diseases (n = 56). A significant proportion of patients with AIH (31%) had elevated levels of autoantibodies to the p53 protein. In contrast, the prevalence of these antibodies in primary biliary cirrhosis (8%) and viral hepatitis (6%) was similar to that in the control group (4%). The clinical features of the anti-p53 seropositive AIH patients were similar to those of the seronegative ones. Thus, the prevalence of p53 autoantibodies in AIH is higher than in other forms of chronic hepatitis, and may be useful in differential diagnosis.     

HLA and GM in insulin-dependent diabetes in the Netherlands: Report on a combined multiplex family and population study

This report deals with the genetic factors involved in insulin-dependent diabetes mellitus (IDD) in The Netherlands. Twenty-two Dutch multiplex families with IDD were typed for HLA-A, -B, -C, and -DR antigens for BF, C2, C4 and GLO polymorphisms, as well as for GM allotypes of immunoglobulins. In addition, 53 unrelated IDD children and 31 unrelated patients with adult onset IDD were typed for HLA-A, -B -C, and -DR antigens. A significant heterogeneity for the frequency of HLA-DR4 related to age of onset was observed. A significant deviation of the Hardy-Weinberg equilibrium was observed for the HLA-DR locus with an excess in patient of heterozygotes HLA-DR3, -DR4, HLA-B8 amd HLA-B15 were not only secondary associated, but constituted with HLA-DR3 and -DR4, respectively, a haplotype in association with IDD. Nonrandom segregation of HLA-haplotypes was observed in multiplex families ex-emplified by an excess of HLA-identical affected sibpairs. Cross-over between HLA-DR and GLO identified the HLA-DR segment as mainly invovled in the association with IDD. Three diabetic haplotypes were confirmed to occur frequently among affected sibs: (a) A1, B8, BFS, C2.1 C4AQ0, C4B1, DR3, GLO2; (b) Aw30, Cw5, B18, BFF1, 22, C4A3, C4BQ0, DR3, GLO2; (c) A2, Cw3, B15, BFS, C2.1, C4A3, C4B3, DR4, GLO1, The segregation of GM allotypes to affected sibpairs was not significantly different from random segregation. The main conclusions from this study are that significant heterogeneity for age of onset exists and that the data are not compatible with simple genetic models including dominant, recessive, and intermediate models of inheritance. The data do require more complex models, involving two different HLA-linked (sets of) susceptibility genes.     

Pancreatic islet and other autoantibodies in juvenile and adult onset diabetics in Australia

The prevalence of serum antibodies to the cytoplasm of the pancreatic islet cell (PICA), and of thyroid microsomal (TMA), gastric parietal cell (GPCA) and anti-nuclear (ANA) antibodies was studied in 135 newly diagnosed diabetics presenting to a hospital for adults and 83 children with recent onset diabetes presenting to a children's hospital. The study also included another 144 diabetic children whose disease had been present longer, and 200 control children. There was a high prevalence (87%) of PICA in the children whose diabetes had just been diagnosed in comparison with control children (1%):(P less than .0001). Diabetic children also had a high prevalence (21%) of one or more of the other autoantibodies in comparison with the control children (9%):(P less than .001). Only 26% of the 58 insulin dependent adults had PICA but 33% had other autoantibodies. Two (3%) of the 77 adult diabetics who did not require insulin had PICA; 8% had other autoantibodies.     

Significance of anti-nuclear and anti-extracellular matrix autoantibodies for albuminuria in murine lupus nephritis; a longitudinal study on plasma and glomerular eluates in MRL/l mice

The relationship between autoantibody reactivities and nephritis in systemic lupus erythematosus (SLE) is unclear. We studied MRL/l mice which developed a considerable albuminuria (either mice with short (< 1 week) or heavy and prolonged (3 weeks) albuminuria) and compared them with non-albuminuric age-matched controls, with young (12 weeks old) non-albuminuric mice and with mice which were followed for 36 weeks and did not develop albuminuria. In a longitudinal prospective study on plasma samples we correlated a variety of anti-nuclear reactivities and reactivities against extracellular matrix (ECM) components, with the onset of albuminuria. We found that at the onset of albuminuria, anti-DNA was higher while anti-nucleosome and anti-H2A/H2B-DNA subnucleosome reactivities were lower compared with age-matched non-albuminuric mice. We also studied glomerular eluates of these mice in ELISA and in indirect immunofluorescence (IF). In the eluates we found with IF that anti-glomerular basement membrane (GBM)-tubular basement membrane (TBM) antibodies were already present in 12-week-old non-albuminuric mice. These eluates showed no anti-nuclear antibodies. In eluates of albuminuric mice more immunoglobulin was deposited, and anti-ECM, anti-DNA and anti-nucleosome reactivities were higher than in eluates of age-matched non-albuminuric mice. The deposition of anti-nucleosome antibodies preceded the deposition of anti-DNA antibodies since they were deposited to a greater extent in mice with a short albuminuria. We conclude that anti-GBM-TBM antibodies are the first autoantibodies that deposit in glomeruli of MRL/l mice at an early age. The onset of albuminuria is associated with additional deposition of both anti-ECM and anti-nuclear (anti-nucleosome and anti-DNA) antibodies, but the difference with non-albuminuric mice seems to be more quantitative than qualitative.     

Cytokeratin autoantibodies: useful serologic markers for toluene diisocyanate-induced asthma

To evaluate the clinical significance of autoantibodies to three major epithelial cytokeratins (CK)--CK8, CK18, and CK19--we compared 66 patients with toluene diisocyanate (TDI)-induced asthma (group I) with three control groups: 169 asymptomatic exposed subjects (group II), 64 patients with allergic asthma (group III), and 123 unexposed healthy subjects (group IV). Serum IgG, specific for human recombinant CKs, were measured by ELISA (enzyme linked immunosorbent assay), and ELISA inhibition tests were performed. The existence of these antibodies was confirmed by IgG immunoblot analysis. Anti-TDI-HSA (human serum albumin) IgE and IgG antibodies were measured by ELISA in the same set of the patients. The prevalence of CK8, CK18, and CK19 auotantibodies in group I was significantly higher than in the other three groups. Results of the ELISA inhibition test showed significant inhibition with the addition of three CKs in a dose-dependent manner. No significant association was found between CK autoantibodies and the prevalence of anti- TDI-HSA IgG and IgE antibodies. These results suggest that autoantibodies to CK18 and CK19 can be used as serologic markers for identifying patients with TDI-induced asthma among exposed workers.     

Autoantibody disturbances in affective disorders: a function of age and gender?

BACKGROUND: Numerous investigators have reported increased autoantibodies to a wide variety of native antigens in patients with affective disorders. However, association of autoimmunity with affective subtypes, mood state, psychotropic medications, age, and gender has not been extensively explored. METHODS: The present study assessed 79 bipolar I, 24 bipolar II, and 46 unipolar major depression patients along with 22 healthy, nonpsychiatric controls for the presence of serum antinuclear (ANA), anti-double stranded DNA, antithyroid microsomal, antithyroglobulin, anticardiolipin (ACA) IgM, and ACA IgG antibodies. RESULTS: Consistent with their higher prevalence of autoimmune disease, women exhibited increased levels of ANA and ACA IgM compared to men. ACA IgG antibody titers also increased significantly with age. Contrary to prior reports of general, overall increases in autoantibodies and specific increases in ANA and antithyroid antibodies in depressed patients, we did not see a significant association between any of the autoantibodies and affective subtype, mood state, or psychotropic medications. LIMITATIONS: Affective subgroups were heterogeneous with respect to psychotropic medications, affective state, age, and gender in this retrospective analysis. Subgroup sample size was insufficient to determine whether interactions of these clinical variables may have influenced results. CONCLUSION: These results suggest that gender and age may have more influence on autoantibodies than affective diagnosis, affective state, or medications.