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PubMed1996

Modulating autoimmune responses to GAD inhibits disease progression and prolongs islet graft survival in diabetes-prone mice.

In nonobese diabetic (NOD) mice, beta-cell reactive T-helper type 1 (Th1) responses develop spontaneously and gradually spread, creating a cascade of responses that ultimately destroys the beta-cells. The diversity of the autoreactive T-cell repertoire creates a major obstacle to the development of therapeutics. We show that even in the presence of established Th1 responses, it is possible to induce autoantigen-specific anti-inflammatory Th2 responses. Immune deviation of T-cell responses to the beta-cell autoantigen glutamate decarboxylase (GAD65), induced an active form of self-tolerance that was associated with an inhibition of disease progression in prediabetic mice and prolonged survival of syngeneic islet grafts in diabetic NOD mice. Thus, modulation of autoantigen-specific Th1/Th2 balances may provide a minimally invasive means of downregulating established pathogenic autoimmune responses.

Adoptive Transfer↗
PubMed1998

Antiepiligrin cicatricial pemphigoid represents an autoimmune response to subunits present in laminin 5 (alpha3beta3gamma2).

Sera from 20 patients with antiepiligrin cicatricial pemphigoid were studied to define the specific reactivity of their IgG autoantibodies. IgG from all patients bound exclusively to the dermal side of 1 mol/L NaCl split skin and immunoprecipitated laminin 5 (alpha3beta3gamma2) from extracts of human keratinocytes (HKs). Immunoblot studies on purified laminin 5 subunits demonstrated that patient IgG bound alpha3 alone in 16 patients. In two patients, IgG autoantibodies were directed predominantly to the gamma2 subunit, yet showed trace reactivity to alpha3 as well. Sera from two patients did not immunoblot any laminin 5 subunits, their IgG presumably immunoprecipitating laminin 5 via a conformational epitope. Sera from patients with alpha3 subunit-specific IgG immunoprecipitated all subunits of laminin 5 as well as polypeptides of 190 and 200 kDa from the conditioned media of HKs. Preclearance studies and experiments utilizing affinity-purified patient IgG demonstrated that the latter signified laminin 6 (alpha3beta1gamma1) that was bound by cross-reactive alpha3 subunit-specific patient IgG. Sera from patients with gamma2 subunit-specific IgG showed no reactivity to laminin 6, except for faint reactivity provided by low levels of their alpha3 subunit-specific IgG. Taken together, these findings indicate that antiepiligrin cicatricial pemphigoid signifies an autoimmune response to subunits present in laminin 5.

Autoantibodies↗
PubMed2001

Anti-insulin antibodies and the natural autoimmune response in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is characterized by the finding of ample serum autoantibodies. The role and the origin of many of these antibodies are still obscure. The aim of this work was to study the occurrence of anti-insulin antibodies (AIA) in SLE, and to postulate, based on AIA determination, on the mechanisms involved in the production of some autoantibodies in SLE. IgG and lgM AIA, anti-DNA antibodies (ADA) and anti-tetanus toxoid antibodies (ATA) were determined using ELISA in sera and B-lymphocytes culture media of 24 SLE patients, 10 healthy controls and 19 insulin-dependent diabetes mellitus (IDDM) patients. B- and T-lymphocytes were isolated using Ficoll gradient, depleted of T-cells using cyclosporin A, EBV infected and grown in medium. The frequencies of IgM-AIA and IgG-ADA were higher in SLE patients than in healthy controls (P < 0.02 and P < 0.05, respectively). The rate of IgM-AIA in SLE and IDDM was comparable, while IgG-AIA was significantly less common in SLE than in IDDM (P < 0.05). The prevalence of ATA in SLE patients and healthy controls was similar. These findings increase the spectrum of the humoral autoimmune response in SLE and suggest that part of it (natural autoantibodies) is independent of antigen driven response.

Adolescent↗
PubMed1991

Molecular characterization of the Ro/SS-A autoimmune response.

Human Ro/SS-A (Ro) antibodies (anti-Ro) are frequently seen in the circulation of patients with several subsets of photosensitive cutaneous lupus erythematosus (LE) and related disorders. Experimental observations have suggested that anti-Ro reacting with Ro antigens that are expressed abberantly within the epidermis might play a causal role in LE-specific skin disorders such as subacute cutaneous LE (SCLE) and neonatal LE. In this article, we will review the progress that has recently been achieved toward gaining a better understanding of the molecular configuration, genetic regulation, and function of the Ro ribonucleoprotein (RNP) antigenic complex as well as the autoimmune response with which it is associated. Work in this area has recently revealed the existence of multiple Ro autoantigen-bearing polypeptides including a 46-kd Ro protein that is virtually identical to calreticulin, a highly conserved, calcium-binding protein that is normally associated with the endoplasmic reticulum. The implications of these observations with respect to the pathogenesis of anti-Ro-associated LE skin lesions are explored.

Antibodies, Antinuclear↗
PubMed1998

B lymphocytes are crucial antigen-presenting cells in the pathogenic autoimmune response to GAD65 antigen in nonobese diabetic mice.

Recent reports have shown that B cells play a key role in the pathogenesis of T cell-mediated autoimmune diseases such as insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic mice (NOD). We have investigated the role of B lymphocytes as APCs in the generation of autoreactive T cell responses by comparing spontaneous responses to self Ags in B cell-deficient and wild-type NOD mice. We determined that B cell-deficient mice had no spontaneous responses to 65-kDa glutamate decarboxylase (GAD65), its immunodominant peptides, and the 60-kDa heat shock protein. In contrast, these Ags are able to induce proliferative responses in the splenocyte cultures of B cell-positive NOD mice. However, T cells from B-deficient mice conserved the ability to respond to nonself Ags and mitogens. The Ag-presenting function of B cells was pivotal in the autoimmune response, since the proliferation of wild-type splenocytes to GAD65 was completely inhibited by blocking the surface Ig-mediated capture of the protein Ag by B cells. Responses to immunodominant GAD65 peptides were also absent in B cell-deficient NOD mice, suggesting that B cells are crucial with regard to the diversification of the autoimmune response to various self epitopes. We believe our results represent strong evidence that B cells are required as APCs to generate pathogenic autoimmune T cell responses and provide a direct correlation between the protection from autoimmune diabetes previously reported in B cell-deficient NOD mice and the lack of anti-GAD65 and anti-heat shock protein 60 T cell responses in these mice.

Animals↗
PubMed1979

Ia-Type alloantigens and humoral autoimmune responsiveness in insulin-dependent diabetes mellitus.

In the search for markers either closely linked to or identical with the hypothetical "diabetogenic major histocompatibility gene," immune region-associated alloantigens were defined in 80 patients with insulin-dependent diabetes and in 107 controls. A close association between the Ia-type alloantigen DRw3 and DRw4 and insulin-dependent diabetes was obtained. DRw3 was found in 36% and DRw4 in 32% of the patients compared to 11% and 16%, respectively, of the controls. In addition, a significant influence of DRw3 and humoral anti-islet-cell autoimmunity could be observed, which was found to be due to a high incidence of DRw3 in those patients with islet cell antibody persistence. Islet-cell antibodies (ICA) were observed in 60% of the DRw3-positive patients compared to only 9% of the DRw3-negatives with longstanding disease (greater than 5 yr). These data show a significant association between insulin-dependent diabetes and the Ia-type alloantigens DRw3 (p uncorr. less than 0.0005) and DRw4 (p uncorr. less than 0.025). Furthermore, they provide direct evidence of an association between an Ia-type alloantigen and persisting humoral autoimmune responsiveness in man.

Antibodies↗
PubMed1993

The HLA-DR and DQ genes control the autoimmune response to DNA topoisomerase I in systemic sclerosis (scleroderma).

HLA class II alleles were determined using the PCR-RFLP method in Japanese systemic sclerosis (scleroderma) patients with (n = 28) or without (n = 34) anti-topoisomerase I antibodies (anti-topo I). Either the DQB1*0601 or *0301 allele was recognized in all anti-topo I positive patients, compared with 44% of anti-topo I negative patients (P < 0.00001, relative risk [RR] > 41) or 58% of Japanese healthy control subjects (P < 0.00001, RR > 24). Tyrosine at position 26 in the second hypervariable region in the beta 1 domain of the DQB1 gene is common to these two alleles and is not present in any other known DQB1 alleles. We also examined immunoreactivities of anti-topo I positive sera to four different autoantigenic B cell epitopes of topo I molecule that were expressed as recombinant fusion proteins. One major B cell epitope, located within the region corresponding to amino acid residues 74-248, was perfectly associated with the amino acid sequence FLEDR at positions 67-71 in the beta 1 domain of the DRB gene. Two other epitopes, corresponding to 316-441 or 658-700, were associated with the serologically defined HLA-DR52 antigen. Patients with both FLEDR and DR52 demonstrated higher anti-topo I antibody titers. These results suggest that the HLA-DR and DQ genes together control the autoimmune response to topo I in systemic sclerosis.

Amino Acid Sequence↗
PubMed1992

[Autoimmune response to thyroglobulin. Proliferative response to thyroglobulin fragments in low responder mice].

Thyroglobulin (Tg) is one of the major thyroid autoantigens involved in autoimmune thyroiditis. The immune response of mice to Tg is genetically controlled by H-2-linked genes. To elucidate the regulation mechanism of autoimmune response to Tg in low responder mice, we studied the proliferative response of lymph node cells (LNC) to mouse Tg (MTg) and enzyme-digested MTg fragments. MTg was treated with Staphylococcus aureus V8 protease followed by separation of the fragments into 6 fractions (Fr1-Fr6: 264,000-17,000) by high performance liquid chromatography (HPLC), LNC from MTg immunized CBA/N (H-2k) mice, a high responder strain, proliferated in response to MTg and all fractions (Fr1-Fr6) of MTg fragments in vitro. In contrast, LNC from MTg immunized BALB/c (H-2d) and B10 (H-2b) mice, low responder strains, did not respond to native Tg but responded well to some smaller Tg fractions (Fr3, 4, 5). In addition, when BALB/c mice were immunized with MTg Fr4 with a molecular weight of 63,000, LNC from BALB/c mice proliferated in response to MTg as well as MTg Fr4. These findings suggest that T cells which are capable of responding to Tg do exist even in low responder mice and that the activation of these autoreactive T cells is suppressed by a regulatory cell subpopulation in low responder mice.

Animals↗
PubMed2002

Interleukin 10 (IL-10) influences autoimmune response in primary Sjögren's syndrome and is linked to IL-10 gene polymorphism.

OBJECTIVE: To investigate the association between serum levels of interleukin 10 (IL-10), the synthesis of autoantibodies, salivary gland disease activity, clinical manifestations, and IL-10 microsatellite polymorphism in patients with primary Sjögren's syndrome (pSS). METHODS: Serum IL-10 and autoantibody levels [IgG anti-Ro and anti-La, total and IgA rheumatoid factor (RF)] were measured by ELISA. A minor salivary gland (MSG) biopsy was performed in all patients and the focus score was determined as a measure of salivary gland disease activity. In addition, IL-10 microsatellite typing was performed by polymerase chain reaction technique. RESULTS: IL-10 concentration was higher in patients (n = 39) than in controls (n = 15) (21.4 +/- 6.7 vs 2.5 +/- 3.5 pg/ml; p = 0.001). We found a significant positive correlation between IL-10 levels and titers of IgA RF, anti-Ro, and anti-La antibodies, as well as focus score. In comparison with patients with low IL-10 production (< 9.5 pg/ml), patients producing high IL-10 had significantly more episodes of cutaneous vasculitis and a higher proportion of them carried the IL-10.G9 allele. CONCLUSION: Autoimmune response in pSS patients as well as salivary gland disease activity and cutaneous involvement appears to be mediated by IL-10 levels; in turn, there is a linkage with IL-10 gene polymorphism.

Adult↗
PubMed1990

Analysis of the autoimmune response in lupus mice: the behaviour and lifespan of anti-DNA-secreting B-cell clones.

We present the results of a study of the physical, haematological and serological features of the progress of the SLE-like syndrome in MRL/Mp-lpr/lpr and (NZB x NZW)Fl mice. As part of this study, we have analysed the IEF spectrotypes of anti-ssDNA antibodies in the sera of these mice and shown that the anti-ssDNA response is clonally restricted, as we have previously shown in a mouse chimaera model and in human SLE. Sequential qualitative and quantitative analysis of anti-ssDNA clonotypes has revealed that the lupus mouse anti-ssDNA clones are relatively short lived, having a lifespan of only 6 to 8 weeks, contrasting sharply with the much longer lifespan previously reported for a mouse anti-DNP-secreting clone and the exceptionally long lifespan of most anti-ssDNA-secreting clones of SLE patients. The implications of these observations for our understanding of the regulation of the autoimmune response are discussed.

Age Factors↗
PubMed2000

Autoimmune response to the thyroid in humans: thyroid peroxidase--the common autoantigenic denominator.

Autoimmunity to thyroid peroxidase (TPO), manifest as high affinity IgG class autoantibodies, is the common denominator of human thyroid autoimmunity, encompassing patients with overt hyper- or hypothyroidism as well as euthyroid individuals with subclinical disease. The identification and cloning of TPO (the "thyroid microsomal antigen") provided the critical tool for analyzing B and T cell reactivity to this major thyroid autoantigen. In particular, the availability of immunoreactive TPO permitted the isolation of essentially the entire repertoire of human monoclonal antibodies, a feat unparalled in an organ-specific autoimmune disease. These recombinant autoantibodies (expressed as Fab) provide insight into the genes encoding their H and L chains as well as the conformational epitopes on TPO with which serum autoantibodies interact. Analyses of TPO autoantibody epitopic "fingerprints" indicate a lack of epitope spreading as well as a genetic basis for their inheritance. Limited data are available for the responses and cytokine profiles of T cells to endogenously processed TPO. Moreover, the role of thyroid cells in initiating the autoimmune response to TPO, and of B cells in expanding and/or modulating the response of sensitized T cells, has yet to be established. Finally, because autoantibody (and likely T cell) responses to TPO parallel those to TSH receptor and thyroglobulin, manipulation of T and B cell responses to TPO may provide the basis for the development of immunospecific therapy for autoimmune thyroid disease in general.

Animals↗
PubMed1998

Polymorphisms of HLA class II genes and autoimmune responses to Ro/SS-A-La/SS-B among Japanese subjects.

OBJECTIVE: To investigate HLA class II allele associations with autoantibody responses to Ro/SS-A and La/SS-B among Japanese subjects. METHODS: Haplotype and allele distributions, along with molecular polymorphisms, of HLA class II genes were analyzed by polymerase chain reaction-restriction fragment length polymorphism in 41 Japanese women with precipitating autoantibodies to Ro/SS-A and/or La/SS-B. RESULTS: Among women with both Ro/SS-A and La/SS-B antibodies, the HLA class II haplotype DRB1*08032/DQA1*0103/DQB1*0601 and DRB1*08032 allele showed significantly increased frequencies compared with patients with anti-Ro/SS-A alone or with normal controls. All women with both anti-Ro/SS-A and anti-La/SS-B, but not those with anti-Ro/SS-A alone, carried DRB1 alleles that shared the same amino acid residues at positions 14-31 and 71 of the hypervariable regions of the DRB1 chain. All anti-Ro/SS-A positive women carried 1 or 2 alleles of DQB1*06 and DQB1*03 subtypes that shared the same amino acid residues at positions 71-77 of the DQB1 chain. HLA class II allele distributions did not differ among 3 anti-Ro/SS-A positive groups with different disease expressions, i.e., patients with systemic lupus erythematosus, patients with primary Sjögren's syndrome, and women with no apparent symptoms of rheumatic disease. CONCLUSION: HLA class II allele distributions differ among anti-Ro/SS-A positive subjects according to the presence or absence of coexisting anti-La/SS-B antibodies, but not according to disease expression. Our findings suggest that different HLA class II molecules might control the development of anti-Ro/SS-A and/or anti-La/SS-B antibodies in the autoimmune response to the Ro/SS-A-La/SS-B complex.

Adolescent↗
PubMed1995

Epstein-Barr virus-induced autoimmune responses. II. Immunoglobulin G autoantibodies to mimicking and nonmimicking epitopes. Presence in autoimmune disease.

During infectious mononucleosis, IgM autoantibodies are generated to a protein, p542, which contains a glycine-rich 28-mer epitope cross-reactive with the Epstein-Barr nuclear antigen-1 through Epstein-Barr nuclear antigen-1's glycine/alanine repeat. In normal individuals it is uncommon to find IgG anti-p542, but among patients with progressive systemic sclerosis, systemic lupus erythematosus, and ulcerative colitis high IgG anti-p542 (> 3 SD above the mean of normal 20-50 yr controls) occurred frequently. Lesser elevations occurred in Sjögren's syndrome, rheumatoid arthritis, ankylosing spondylitis, and Crohn's disease, but none with chronic hepatitis B infection. The reactive epitopes on p542 were mapped with deletion mutants, which indicated that the glycine-rich 28-mer was the major antigenic determinant, with lesser antibody responses to other epitopes. We conclude that normally there is an inability to generate IgG autoantibodies to the cross-reactive (mimicking) epitope of the p542 host protein, but that this inability is overcome in a proportion of patients with autoimmune disease. We conclude also that non-cross-reactive autoepitopes exist on p542 protein, to which IgG autoantibodies can commonly be formed in autoimmune disorders. The mechanisms responsible for the latter must involve different mechanisms than those responsible for autoantibodies to the mimicking epitope.

Adolescent↗
PubMed2000

Patients with bullous pemphigoid and linear IgA disease show a dual IgA and IgG autoimmune response to BP180.

Bullous pemphigoid (BP) and linear IgA disease (LAD) are autoimmune subepidermal blistering skin diseases associated with autoantibodies against the transmembrane hemidesmosomal protein BP180/type XVII collagen. It has been demonstrated previously that BP is characterized predominantly by IgG autoantibodies, while autoantibodies in LAD mainly belong to the IgA isotype. The aim of the present study was to investigate the hypothesis that there is a significant overlap in the autoantibody isotype profiles associated with these two diseases. Several new recombinant forms of BP180 were generated in the baculovirus expression system, including the full-length protein. IgG autoantibodies to BP 180 were detectable in 39 of 40 (98%) of BP sera; interestingly, 88% of BP sera also contained IgA anti-BP180 autoantibodies. Similarly, anti-BP180 reactivity in LAD sera (n=22) was also attributed to both an IgA (68%) and an IgG (76%) autoantibody response. IgA and IgG autoantibodies to the intracellular portion of BP180 were found in 14% and 28% of BP sera, respectively, and in 8% of LAD sera (same percentage for both isotypes). Our findings clearly demonstrate that both BP and LAD patients have a dual IgA and IgG autoimmune response to BP180 which is directed not only to the ectodomain, but also to the intracellular portion of this protein.

Adult↗
PubMed2006

Analysis of T-cell assays to measure autoimmune responses in subjects with type 1 diabetes: results of a blinded controlled study.

Type 1 diabetes is a chronic autoimmune disease mediated by autoreactive T-cells. Several experimental therapies targeting T-cells are in clinical trials. To understand how these therapies affect T-cell responses in vivo, assays that directly measure human T-cell function are needed. In a blinded, multicenter, case-controlled study conducted by the Immune Tolerance Network, we tested responses in an immunoblot and T-cell proliferative assay to distinguish type 1 diabetic patients from healthy control subjects. Peripheral blood cells from 39 healthy control subjects selected for DR4 and 23 subjects with recently diagnosed type 1 diabetes were studied. Autoantibody responses were measured in serum samples. Positive responses in both assays were more common in peripheral blood mononuclear cells from new-onset type 1 diabetic patients compared with control subjects. The proliferative, immunoblot, and autoantibody assays had sensitivities of 58, 91, and 78% with specificities of 94, 83, and 85%, respectively. When cellular assays were combined with autoantibody measurements, the sensitivity of the measurements was 75% with 100% specificity. We conclude that cellular assays performed on peripheral blood have a high degree of accuracy in discriminating responses in subjects with type 1 diabetes from healthy control subjects. They may be useful for assessment of cellular autoimmune responses involved in type 1 diabetes.

Adolescent↗
PubMed1998

Cell-mediated autoimmune response to testis induced by bilateral testicular injury can be suppressed by cyclosporin A.

PURPOSE: Since the delayed type hypersensitivity (DTH) response to testis antigens plays a key role in the induction and/or maintenance of experimental autoimmune orchitis (EAO), an animal model for human immunological male infertility or aspermatogenesis, we have investigated the immunosuppressive effect of cyclosporin A (CsA) on the DTH response to autologous testicular cells (TC). MATERIALS AND METHODS: A DTH response to autologous TC was induced in C3H/HeN mice by bilateral testicular injury (trauma). CsA was administered intraperitoneally for 10 consecutive days before and after injury. A DTH response was assessed by measuring delayed footpad reaction (DFR) to autologous TC 9 days after injury. RESULTS: When the mice were traumatized alone, 10 mg./kg. or more of CsA suppressed the DTH response to autologous TC significantly. In mice traumatized with 100 mg./kg. of cyclophosphamide (CY)-pretreatment, 30 mg./kg. or more of CsA was needed to suppress the DTH response. In mice traumatized with 200 mg./kg. of CY-pretreatment, 50 mg./kg. of CsA was needed to suppress the autoimmune response. CONCLUSIONS: The DTH response to autologous TC was suppressed significantly by administration of CsA in a dose-dependent manner. We have also shown the direct suppressive effect of CsA on effector cells for DTH by means of local passive transfer of DTH. Administration of CsA had no augmenting or suppressive effect on suppressor cells for DTH. CsA might be a significant drug for the immunosuppression of EAO and possibly for immunological male infertility.

Animals↗
PubMed1995

Genetic and epitopic analysis of thyroid peroxidase (TPO) autoantibodies: markers of the human thyroid autoimmune response.

TPO autoantibodies, the hallmark of human autoimmune thyroid disease, are of IgG class and are associated with thyroid destruction and hypothyroidism. Using the immunoglobulin gene combinatorial library approach, a panel of human monoclonal TPO autoantibodies (expressed as Fab) has been generated from thyroid tissue-infiltrating B cells. TPO-specific Fab closely resemble patients' serum autoantibodies in terms of L chain type, IgG subclass, affinities for TPO as well as epitopes recognized by > 80% of TPO autoantibodies in an individual's serum. TPO autoantibody V region genes are not unique; H chain V genes are usually mutated, while L chain V genes are sometimes in germ-line conformation. The autoantibodies recognize an immunodominant region involving conformational, overlapping epitopes in domains A and B. Finally, TPO autoantibody epitopic fingerprints are distinctive for individual sera, are not associated with hypothyroidism, but are conserved over time (indicating a lack of B cell epitope spreading). Evidence for conservation as well as inheritance of the fingerprints in some families, together with VH gene polymorphisms, may provide insight into the genetic basis of human autoimmune thyroid disease. Furthermore, monoclonal human TPO autoantibodies will be invaluable for B cell presentation of TPO to determine the T cell epitopes involved in TPO autoantibody production.

Animals↗