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PubMed1997

Premature ovarian failure and ovarian autoimmunity.

Premature ovarian failure (POF) is defined as a syndrome characterized by menopause before the age of 40 yr. The patients suffer from anovulation and hypoestrogenism. Approximately 1% of women will experience menopause before the age of 40 yr. POF is a heterogeneous disorder with a multicausal pathogenesis involving chromosomal, genetic, enzymatic, infectious, and iatrogenic causes. There remains, however, a group of POF patients without a known etiology, the so-called "idiopathic" form. An autoimmune etiology is hypothesized for the POF cases with a concomitant Addison's disease and/or oöphoritis. It is concluded in this review that POF in association with adrenal autoimmunity and/or Addison's disease (2-10% of the idiopathic POF patients) is indeed an autoimmune disease. The following evidence warrants this view: 1) The presence of autoantibodies to steroid-producing cells in these patients; 2) The characterization of shared autoantigens between adrenal and ovarian steroid-producing cells; 3) The histological picture of the ovaries of such cases (lymphoplasmacellular infiltrate around steroid-producing cells); 4) The existence of various autoimmune animal models for this syndrome, which underlines the autoimmune nature of the disease. There is some circumstantial evidence for an autoimmune pathogenesis in idiopathic POF patients in the absence of adrenal autoimmunity or Addison's disease. Arguments in support of this are: 1) The presence of cellular immune abnormalities in this POF patient group reminiscent of endocrine autoimmune diseases such as IDDM, Graves' disease, and Addison's disease; 2) The more than normal association with IDDM and myasthenia gravis. Data on the presence of various ovarian autoantibodies and anti-receptor antibodies in these patients are, however, inconclusive and need further evaluation. A strong argument against an autoimmune pathogenesis of POF in these patients is the nearly absent histological confirmation (the presence of an oöphoritis) in these cases (< 3%). However, in animal models using ZP immunization, similar follicular depletion and fibrosis (as in the POF women) can be detected. Accepting the concept that POF is a heterogenous disorder in which some of the idiopathic forms are based on an abnormal self-recognition by the immune system will lead to new approaches in the treatment of infertility of these patients. There are already a few reports on a successful ovulation-inducing treatment of selected POF patients (those with other autoimmune phenomena) with immunomodulating therapies, such as high dosages of corticosteroids (288-292).

Addison Disease↗

PubMed2001

Neuronal survival after CNS insult is determined by a genetically encoded autoimmune response.

Injury to the CNS is often followed by a spread of damage (secondary degeneration), resulting in neuronal losses that are substantially greater than might have been predicted from the severity of the primary insult. Studies in our laboratory have shown that injured CNS neurons can benefit from active or passive immunization with CNS myelin-associated antigens. The fact that autoimmune T-cells can be both beneficial and destructive, taken together with the established phenomenon of genetic predisposition to autoimmune diseases, raises the question: will genetic predisposition to autoimmune diseases affect the outcome of traumatic insult to the CNS? Here we show that the survival rate of retinal ganglion cells in adult mice or rats after crush injury of the optic nerve or intravitreal injection of a toxic dosage of glutamate is up to twofold higher in strains that are resistant to the CNS autoimmune disease experimental autoimmune encephalomyelitis (EAE) than in susceptible strains. The difference was found to be attributed, at least in part, to a beneficial T-cell response that was spontaneously evoked after CNS insult in the resistant but not in the susceptible strains. In animals of EAE-resistant but not of EAE-susceptible strains devoid of mature T-cells (as a result of having undergone thymectomy at birth), the numbers of surviving neurons after optic nerve injury were significantly lower (by 60%) than in the corresponding normal animals. Moreover, the rate of retinal ganglion cell survival was higher when the optic nerve injury was preceded by an unrelated CNS (spinal cord) injury in the resistant strains but not in the susceptible strains. It thus seems that, in normal animals of EAE-resistant strains (but not of susceptible strains), the injury evokes an endogenous protective response that is T-cell dependent. These findings imply that a protective T-cell-dependent response and resistance to autoimmune disease are regulated by a common mechanism. The results of this study compel us to modify our understanding of autoimmunity and autoimmune diseases, as well as the role of autoimmunity in non-autoimmune CNS disorders. They also obviously have far-reaching clinical implications in terms of prognosis and individual therapy.

Animals↗

PubMed1999

Koch's postulates and autoimmunity: an opposing viewpoint.

Autoimmunity is characterized as a state of abnormal specific humoral and cell-mediated responses against constituents of body tissues. One time-honored approach to explaining the pathogenesis of autoimmunity has been application of the Koch's postulates, on loan from the field of microbiology suggesting that autoantibodies and/or autoreactive T cells are the presumed "pathogens" of autoimmunity, and that passive transfer of these autoimmune factors to susceptible animals will result in the induction of the autoimmune disease. We suggest that autoimmunity is not in many cases due to the presence of factors leading to the autoimmune response in those susceptible. Instead, it is the lack of a factor which leads to the development of autoimmunity, a factor (cytokine, protein, gene, etc.) which is present in the healthy individual and normally protects in from disordered immune regulation. We propose to direct more research into therapeutic modulation of autoimmunity by administration of putative "protective factors", rather than by attempts to depress or remove autoreactive cells and antibodies from the autoimmune.

Adoptive Transfer↗

PubMed2005

Familial aggregation of systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune diseases in 1,177 lupus patients from the GLADEL cohort.

OBJECTIVE: To determine whether there is familial aggregation of systemic lupus erythematosus (SLE) and/or other autoimmune diseases in SLE patients and to identify clinical differences between patients with and those without familial autoimmunity. METHODS: We interviewed members of the Grupo Latinoamericano de Estudio del Lupus Eritematoso (GLADEL) inception cohort of 1,214 SLE patients to ascertain whether they had relatives with SLE and/or other autoimmune diseases. Identified relatives were studied. Familial aggregation was tested using reported highest and intermediate population prevalence data for SLE, rheumatoid arthritis (RA), or all autoimmune diseases, and studies were performed to identify the genetic model applicable for SLE. RESULTS: We identified 116 first-, second-, or third-degree relatives with SLE, 79 with RA, 23 with autoimmune thyroiditis, 3 with scleroderma, 1 with polymyositis, and 16 with other autoimmune diseases, related to 166 of the 1,177 SLE patients in the GLADEL cohort who agreed to participate. Forty-two SLE patients had 2 or more relatives with an autoimmune disease. We found a lambda(sibling) of 5.8 and 29.0 for SLE and of 3.2-5.3 for RA, when comparing with their reported high or intermediate population prevalence, respectively. We also found familial aggregation for autoimmune disease in general (lambda(sibling) = 1.5) and determined that for SLE, a polygenic additive genetic model, rather than a multiplicative one, is applicable. CONCLUSION: In SLE there is familial aggregation of SLE, RA, and autoimmune disease in general. A polygenic additive model applies for SLE. American Indian-white Mestizo SLE patients and those with higher socioeconomic level were more likely to have familial autoimmunity.

Arthritis, Rheumatoid↗

PubMed1996

The autoimmune reactivity to myelin oligodendrocyte glycoprotein (MOG) in multiple sclerosis is potentially pathogenic: effect of copolymer 1 on MOG-induced disease.

Multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS) characterized by primary demyelination, is believed to result from an autoimmune attack against myelin components. In view of their ability to induce experimental autoimmune encephalomyelitis (EAE), an animal model for MS, the quantitatively major malign proteins--myelin basic protein (MBP) and proteolipid protein (PLP)--have been extensively studied as the relevant primary antigens in MS, and therapeutic approaches have been targeted to counteract autoimmune reactivity to MBP and PLP. Accordingly, copolymer 1, a random synthetic amino acid copolymer crossreactive with MBP and highly protective against the induction of EAE with MBP or PLP, is not being extensively tested in clinical studies as a therapeutic agent for MS. However, increasing evidence suggests that autoimmune reactivity against other CNS-specific myelin proteins could also be involved in the pathogenesis of MS. In this context, we have demonstrated that peripheral blood lymphocytes from patients with MS respond predominantly to myelin oligodendrocyte glycoprotein (MOG) rather than to MBP or PLP, suggesting an important role for cell reactivity against MOG in the pathogenesis of MS. We have demonstrated that T-cell reactivity in MOG can also be pathogenic by inducing neurological disease in H-2u and H-2b mice with the same peptide of MOG, pMOG 35-55. Most interestingly, the expression of the disease differed with the different MHC backgrounds. Induction of a differentially expressed disease in different strains of mice with the same myelin antigen makes this new model particularly relevant to MS, where different expression of the disease is seen in different patients. Therefore, notwithstanding the importance of the autoimmune reactivity to MBP and PLP in MS, the potentially pathogenic autoimmune reactivity to MOG must now also be taken into consideration in therapeutic approaches to MS. In this context, we have investigated the possible effect of copolymer 1 treatment on autoimmune reactivity to MOG and on the development of EAE induced by MOG. Copolymer 1 was found to inhibit the binding of MOG peptides to MHC molecules, as well as the proliferation of MOG-reactive T cells, in a dose-dependent manner. In parallel, injection of copolymer 1 concomitantly with the encephalitogenic MOG peptide exerted a strong protective effect against the development of EAE. These preliminary data on the effect of copolymer 1 on the autoimmune response to MOG in mice indicate that copolymer 1 may also be effective in cases of MS where the autoimmune response to MOG prevails, and should therefore be further investigated in this context.

Animals↗

PubMed1988

The reproductive autoimmune failure syndrome.

The association between reproductive failure and abnormal autoimmune function has been recognized for decades in association with such established autoimmune diseases as systemic lupus erythematosus. Recent investigations have expanded this association to women who demonstrate similar humoral abnormalities as patients with defined autoimmune diseases but do not express any of the clinical symptoms required for the diagnosis of an autoimmune disease. The observation that abnormal autoimmune function in clinically asymptomatic patients can lead to reproductive failure has led us to define the reproductive autoimmune failure syndrome as a diagnostic entity. The present article summarizes evidence suggesting that the occurrence of reproductive autoimmune failure syndrome may be teleologically related to the woman's need for increased self-tolerance in face of antigenic exposure to the maternal haplotype of the fetus during normal pregnancy. This need for increased self-tolerance is documented by higher normal autoantibody levels in women than in men and may also be responsible for the highly increased incidence of autoimmune diseases in women in comparison with men. Under this concept, abnormal autoimmune function may lead to reproductive failure at different stages of the reproductive process, depending on the quality and possibly quantity of the abnormal autoimmune response.

Abortion, Habitual↗

PubMed1992

Anti-GOR and hepatitis C virus in autoimmune liver diseases.

Anti-GOR is an autoantibody found in hepatitis C virus (HCV) infection. We have studied the specificity of this antibody for HCV infection in various groups of autoimmune liver diseases. Anti-HCV was detected by a second generation HCV enzyme-linked immunosorbent assay in 14 of 29 patients with liver-kidney-microsomal (LKM-1) -antibody-positive autoimmune hepatitis type 2 and in all 6 control patients with HCV-RNA-positive chronic hepatitis C. Anti-HCV was not found in those with antinuclear-antibody-positive autoimmune hepatitis type 1 (10 patients), with soluble-liver-protein-antibody-positive autoimmune hepatitis type 3 (8), with primary biliary cirrhosis (9), with systemic lupus erythematosus (SLE) (10), or in healthy controls (13). Anti-GOR was detected in 11 of 14 patients with autoimmune hepatitis type 2 who were all positive for anti-HCV but only in 1 of 15 LKM-1 patients who were negative for anti-HCV. We did not find anti-GOR in any other group of autoimmune liver disease, SLE, or control sera, but this antibody was detected in 3 of 6 patients with chronic hepatitis C. Autoimmune hepatitis type 2 patients who were anti-GOR positive and anti-HCV positive were less likely to be female, were older (p less than 0.001), and had lower LKM-1 antibody titres (p less than 0.001), lower disease activity, and responded less effectively to immuno- suppression than did those who were anti-HCV negative/anti-GOR negative. The findings show that anti-GOR reflects HCV-specific autoimmunity. HCV seems to induce autoimmunity to both GOR (an HCV-specific autoepitope) and LKM-1 (an epitope that is also recognised by autoimmune hepatitis sera of a different cause). Anti-GOR and LKM-1 antibodies contribute to a better differentiation of chronic hepatitis, a finding that has therapeutic implications.

Adolescent↗

PubMed1995

Anti-actin antibodies in sera from patients with autoimmune liver diseases and patients with carcinomas by ELISA.

UNLABELLED: Smooth muscle antibodies (SMA) were initially detected in sera of patients with chronic active hepatitis (CAH). Subsequently, their presence was demonstrated in a wide variety of other diseases. SMA are a mixture of antibodies directed towards different cytoskeletal antigens. Sera with high titers of anti-actin antibodies (AAA), a subgroup of SMA, are most frequently found among patients with autoimmune chronic active hepatitis (CAH) and, to a lesser extent, among patients with primary biliary cirrhosis (PBC) and other diseases. It is therefore established that AAA are a reliable marker to autoimmune CAH. The purpose of this study was to determine the titer of AAA in sera of patients with liver, autoimmune diseases and carcinomas, using the enzyme-linked immunoabsorbent assay (ELISA) method. The results were expressed as the optical density (OD) of the examined sera divided by the OD of a sera from a healthy control (presented as percentages +/- standard deviation). Sera of 33 patients with cirrhosis, nine patients with autoimmune CAH, fifteen patients with non-autoimmune CAH, eight patients with PBC, 30 patients with Sjogren's syndrome, 60 patients with SLE, 142 patients with carcinomas of different kinds, and 34 healthy donors were examined for the presence of AAA by ELISA. Statistically significant (P < 0.003) higher titers of AAA were detected in patients with autoimmune CAH (57 +/- 23%) compared with the control group and to other groups of diseases. AAA titers in non-autoimmune CAH were not significantly higher compared to the control group. High titers of AAA were detected in 67% of the patients with autoimmune CAH, as compared with other diseases in which only up to 13% of the patients exhibited AAA positivity. CONCLUSION: existence of higher levels of AAA noted in 67% of the patients with autoimmune CAH with regard to other groups of diseases, emphasizes the value of AAA as sensitive and specific markers, capable of characterizing the patients with autoimmune chronic active hepatitis.

Actins↗

PubMed2006

The impact of abnormal autoimmune function on reproduction: maternal and fetal consequences.

The impact of abnormal autoimmune function on reproductive success has remained a highly controversial issue. This is, at least partially, due to the relative lack of demographic data from women with established autoimmune diseases. We, therefore, investigated 163 women with proven autoimmune diseases and 73 controls in a demographic study of reproductive success and impact of abnormal autoimmunity on pregnancy and offspring. Women with autoimmune diseases experienced fewer pregnancies overall (p=0.04) and fewer pregnancy losses (p=0.05). Offspring from women with autoimmune diseases demonstrated a significantly increased prevalence of confirmed autoimmune diseases (p=0.04; OR 3.759; 95%CL 1.04-1.27), which increased further if suspected, but not yet confirmed, cases were added (p=0.001; OR 8.592; 95%CL 1.05-55.0). Women with autoimmune diseases exhibited a trend towards lower cesarean section delivery during their own birth and a significantly increased prevalence of disease in vaginally delivered offspring (p=0.014; OR 6.041; 95%CL 1.32-38.22). Autoimmune diseases impair female fecundity even before the diseases become clinically overt. Offspring are at increased risk to develop autoimmune diseases, though they may differ from those of their mothers. This risk appears to correlate with mode of delivery and may be the consequence of varying cell traffic dynamics with vaginal and cesarean section deliveries.

Adult↗

PubMed1997

Hepatitis C virus infection and autoimmunity.

Hepatitis C virus (HCV) infection has been associated with a plethora of immune and autoimmune perturbations. We review serological and clinical autoimmune manifestations associated with HCV infection, discuss treatment regimens for HCV-related autoimmune diseases, and present a framework for understanding HCV-associated autoimmune disease by performing a computerized literature search from which representative articles were used and referenced. The immune response to HCV may include the development of cryoglobulins, rheumatoid factor, antinuclear antibodies (ANA), anticardiolipin, antithyroid, anti-liver/kidney/microsomal antibodies (anti-LKM), as well as HCV/anti-HCV immune complex formation and deposition. HCV infection is a significant cause of mixed essential cryoglobulinemia, which may then be complicated by cryoglobulinemic glomerulonephritis, vasculitis, or neuropathy. It has also been associated with membranous and membranoproliferative glomerulonephritis. Subsets of autoimmune hepatitis patients are infected with HCV and evidence suggests that HCV is a causative agent of antithyroid antibodies and autoimmune thyroid disease. Although cause-and-effect remain to be proved, there are reports of HCV infection preceding or coincident with polyarthritis, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and polymyositis/dermatomyositis (PM/DM). HCV-infected patients also have a high incidence of sialoadenitis, and reports of low-grade lymphoproliferative malignancies have emerged. However, HCV is not a major causative factor for most autoimmune diseases. Optimal treatment for HCV-related autoimmune disease remains to be determined. Interferon alpha (IFN alpha) has successfully reduced viremia/transaminitis, cryoglobulins, proteinuria, and nephritis, but recurrent disease manifestations are frequent after discontinuation of therapy. Moreover, IFN alpha may precipitate or exacerbate autoimmune disease symptoms. HCV-related autoimmune disease also has been treated successfully with corticosteroids, azathioprine, and cyclophosphamide, although HCV viremia persists and may worsen.

Antibodies, Viral↗

PubMed1983

Role of aberrant HLA-DR expression and antigen presentation in induction of endocrine autoimmunity.

Immune responses are initiated by HLA-DR+ cells, which present antigen to T cells. Observations that HLA-DR may be experimentally induced on thyroid epithelium and that HLA-DR occurs on thyrocytes in autoimmune thyroid diseases suggest a mechanism of autoimmunity with special relevance to organ-specific diseases. This involves the local aberrant expression of HLA-DR antigens by epithelial cells and their subsequent capacity to present autoantigens occurring on their surfaces to T lymphocytes. For autoantigens which T cells recognise infrequently because of their restricted tissue location and low concentration in the circulation, T-cell tolerance is unlikely, and so induction of autoreactive T cells would occur. Because interferon is the best known inducer of DR antigen expression and viral infections may predate endocrine autoimmunity, the following sequence seems likely: local viral infection which causes interferon production, or other local environmental factors which would induce DR expression, presentation of autoantigens, and subsequent autoimmune T-cell induction. These T cells would activate effector B and T cells. Whether the initial induction of autoimmune T cells leads to autoimmune disease would depend on factors such as abnormalities of the suppressor T-cell pathway, reported to coexist with autoimmunity and necessary to induce autoimmune disease in mice. This mechanism of autoimmune disease induction explains vague associations with viral infections and long latency periods before disease becomes manifest and gives a simple explanation for the well-documented association between HLA-DR and autoimmune diseases in man.

Autoantigens↗

PubMed2003

Modulation of D-penicillamine-induced autoimmunity in the Brown Norway rat using pharmacological agents that interfere with arachidonic acid metabolism or synthesis of inducible nitric oxide synthase.

The D-penicillamine-induced autoimmune syndrome observed in Brown Norway (BN) rats is similar to an idiosyncratic reaction seen in some patients. We have previously shown that pretreatment of BN rats with aminoguanidine, an inducible nitric oxide synthase (iNOS) inhibitor, and misoprostol, a prostaglandin E (PGE) analog, completely prevented the development of D-penicillamine-induced autoimmunity. In an effort to further understand the role of arachidonic acid metabolism and iNOS in the pathogenesis of D-penicillamine-induced autoimmunity we had 3 objectives: (1) to test whether aminoguanidine and misoprostol could reverse D-penicillamine-induced autoimmunity; (2) whether BN rats that had previously developed D-penicillamine-induced autoimmunity could be protected on re-challenge with drug by pretreatment with aminoguanidine and misoprostol and (3) whether non-steroidal anti-inflammatory drugs, which inhibit PGE synthesis, would potentiate D-penicillamine-induced autoimmunity. We found that neither aminoguanidine nor misoprostol had any significant effect on the speed of recovery from D-penicillamine-induced autoimmunity. Prevention of disease on re-challenge after a 4 week recovery was less effective than on initial treatment with 7/8 animals pretreated with aminoguanidine getting sick again, while only 5/13 animals pretreated with misoprostol became ill. The effect of aminoguanidine was not significantly different from control (16/17) but that of misoprostol was (P=0.002). A single dose of the non-selective cyclooxygenase (COX) inhibitor, ketoprofen, decreased the time to onset of D-penicillamine-induced autoimmunity and continuous treatment significantly increased the incidence (P=0.024). Diclofenac, which is more selective, did not have a significant effect, and one dose of the selective inhibitor, rofecoxib, actually appeared to lower the incidence of D-penicillamine-induced autoimmunity (P=0.001). In this animal model of drug-induced autoimmunity, non-selective COX inhibitors appear to increase the incidence of disease. However, once the reaction occurs, prostaglandins are not effective for treatment and are only partially protective in an already sensitized animal.

Animals↗

PubMed1999

Autoimmunity induced by interferon-alpha therapy for chronic viral hepatitis.

Type I interferons, which are mostly alpha-interferons (either as single agents or in combination with antiviral drugs), are currently the standard therapy for chronic viral hepatitis B, B/D, and C. Side-effects are not uncommon and include exacerbation of pre-existing autoimmune disorders or the de novo induction of autoimmunity. These adverse effects are attributed to the immunomodulatory properties of type I interferons, and should be distinguished from autoimmunity associated with chronic viral hepatitis in which interferon treatment may indeed be beneficial. The major autoimmune side-effects of interferon therapy for chronic viral hepatitis are thyroid or liver disease. Therefore, screening for thyroid antibodies and auto-antibodies indicative of autoimmune hepatitis both before, during, and after interferon therapy is strongly recommended. The presence of high concentrations of thyroid auto-antibodies or antibodies associated with autoimmune hepatitis can be contraindicative to interferon therapy. However, treatment is not contraindicated in viral hepatitis (in particular chronic hepatitis C) associated with autoimmune phenomena--including low-titer thyroid antibodies or other non-organ specific auto-antibodies. If interferon-induced autoimmunity occurs, the necessity of therapy has to be balanced carefully against the risks of autoimmune disease. Further research is needed to identify the factors which determine susceptibility to interferon-associated autoimmunity in individual patients.

Autoimmunity↗

PubMed2006

Clustering of autoimmune diseases in families with a high-risk for multiple sclerosis: a descriptive study.

BACKGROUND: Autoimmune mechanisms are thought to have a major role in the pathogenesis of multiple sclerosis. We aimed to identify coexisting autoimmune phenotypes in patients with multiple sclerosis from families with several members with the disease and in their first-degree relatives. METHODS: A total of 176 families (386 individuals and 1107 first-degree relatives) were characterised for a history of other autoimmune disorders. Family-based or case-control analyses were done to assess the association of cytotoxic T-lymphocyte-antigen 4 (CTLA4) and protein tyrosine phosphatase (PTPN22) variants with susceptibility to multiple sclerosis. FINDINGS: 46 (26%) index cases reported at least one coexisting autoimmune disorder. The most common were Hashimoto thyroiditis (10%), psoriasis (6%), inflammatory bowel disease (3%), and rheumatoid arthritis (2%). 112 (64%) families with a history of multiple sclerosis reported autoimmune disorders (excluding multiple sclerosis) in one or more first-degree relatives, whereas 64 (36%) families reported no history of autoimmunity. Similar to index cases, Hashimoto thyroiditis, psoriasis, and inflammatory bowel disease were also the most common disorders occurring in family members. A common variant within CTLA4 was strongly associated with multiple sclerosis in families who had other autoimmune diseases (p=0.009) but not in families without a history of other autoimmune disorders (p=0.90). INTERPRETATION: The presence of various immune disorders in families with several members with multiple sclerosis suggests that the disease might arise on a background of a generalised susceptibility to autoimmunity. This distinct multiple-sclerosis phenotype, defined by its association with other autoimmune diseases, segregates with specific genotypes that could underlie the common susceptibility.

Alleles↗

PubMed1996

HLA DRB1/DQA1/DQB1 haplotype determines thyroid autoimmunity in patients with insulin-dependent diabetes mellitus.

OBJECTIVE: Thyroid autoimmunity is frequently associated with insulin-dependent diabetes mellitus (IDDM). The genetic factors which contribute to thyroid autoimmunity and IDDM have been described but vary between different races. We have therefore investigated the effect of class II HLA genes at both loci and the HLA haplotypes on the presence of autoimmunity in patients with IDDM in Taiwan. SUBJECTS AND MEASUREMENTS: Eighty-three patients with IDDM and 105 unrelated normal controls were recruited for the measurement of thyroid autoantibodies and for genotyping of HLA DRB1, DQA1 and DQB1 by polymerase chain reaction-based DNA typing techniques. RESULTS: Among 83 patients with IDDM, 23 (27.7%) were positive for antithyroid autoantibodies. Compared to those without thyroid autoimmunity, there was a female preponderance for IDDM with thyroid autoimmunity (female: male, 3:20 vs 29:31). Among the DR specificities, DR6 was associated with a weak protective effect against thyroid autoimmunity in IDDM patients. Upon detailed analysis of class II HLA haplotypes, the DRB1*0301/ DQA1*0501/DQB1*0201 haplotype was found to be associated with an increased risk of IDDM regardless of thyroid autoimmunity, while DRB1*0405/DQA1*0301/ DQB1*0401 was significantly increased only in the IDDM patients with thyroid autoimmunity. IDDM individuals with the HLA DRB1*0405/DQA1*0301/DQB1*0302 haplotype were not at risk of thyroid autoimmunity. CONCLUSIONS: Our data indicated that there was a generalized genetic factor within or associated with the DRB1*0301/DQA1*0501/DQB1*0201 haplotype, and a more restricted effect with the DRB1*0405/DQA1*0301/DQB1*0401 haplotype which led to thyroid autoimmunity in patients with insulin-dependent diabetes mellitus.

Adolescent↗

PubMed2000

Angiotensin converting enzyme (ACE) gene polymorphism in sarcoidosis in relation to associated autoimmune diseases.

OBJECTIVES: To investigate the significance of ACE gene insertion/deletion (I/D) polymorphism in the frequency of autoimmune manifestations in sarcoidosis. DESIGN: In patients with sarcoidosis the ACE gene I/D polymorphism was detected with PCR on genomic DNA. The patients with sarcoidosis were divided according to the presence (n = 30) or absence (n = 32) of autoimmune manifestations. The former group was subdivided into thyroid autoimmunity (n = 10), gluten immune reactivity (n = 10) and gastric autoimmunity (n = 17). SETTINGS: The patients were recruited at the Department of Pulmonary Medicine, and the study was conducted at the Department of Endocrinology, University of Lund, Malmö University Hospital, Malmö, Sweden. SUBJECTS: Sixty-two patients with documented sarcoidosis (30 females, 32 males, median age/range at diagnosis of sarcoidosis 31.5/19-75 years, median age/range at study 47.5/22-81 years) were examined. A total of 107 healthy unrelated subjects without sarcoidosis (60 females, 47 males, median age/range at study 58/40-82 years) served as controls. RESULTS: S-ACE values were significantly increased in patients compared to controls (P = 0.00001). The same was true in the subgroup of sarcoidosis patients with associated autoimmunity compared with those with isolated sarcoidosis (P = 0.0328). A significant association was seen between ACE gene polymorphism (II, ID, DD genotypes) and S-ACE levels in both patients and controls according to the order II < ID < DD. The observed genotype frequency distributions in the different study groups agreed the Hardy-Weinberg equilibrium without significant differences between the patients and the controls. Within the group with autoimmune manifestations the DD genotype was significantly over-represented in X-ray stage III compared to the other X-ray stages (P = 0.0181) and a significant increase in the DD genotype in X-ray stage III (P = 0.035) in the group with autoimmune manifestations compared to isolated sarcoidosis was detected. CONCLUSION: We confirmed that the S-ACE levels corresponded to the order II < ID < DD in patients with sarcoidosis as well as in healthy controls. S-ACE levels were significantly higher in sarcoidosis patients with autoimmune manifestations. The frequency of the DD genotype was significantly increased in patients with autoimmune manifestations and major granuloma mass (X-ray stage III). The ACE D allele in its homozygous form may confer susceptibility for autoimmune manifestations in sarcoidosis, possibly via the high levels of S-ACE it encodes.

Adult↗

PubMed2002

The role of CD4+CD25+ immunoregulatory T cells in the induction of autoimmune gastritis.

A number of experimental models of organ-specific autoimmunity involve a period of peripheral lymphopenia prior to disease onset. There is now considerable evidence that the development of autoimmune disease in these models is due to the absence of CD4+CD25+ regulatory T cells. However, the role of CD4+CD25+ regulatory T cells in the prevention of autoimmune disease in normal individuals has not been defined. Here we have assessed the affect of depletion of CD4+CD25+ regulatory T cells in BALB/c mice on the induction of autoimmune gastritis. The CD4+CD25+ T cell population was reduced to 95% of the original population in adult thymectomized mice by treatment with anti-CD25 mAb. By 48 days after the anti-CD25 treatment, the CD4+CD25+ regulatory T cell population had returned to a normal level. Treatment of thymectomized adult mice for up to 4 weeks with anti-CD25 mAb did not result in the development of autoimmune gastritis. Furthermore, we have demonstrated that depletion of CD4+CD25+ regulatory T cells, together with transient CD4+ T lymphopenia, also did not result in the development of autoimmune gastritis, indicating that peripheral expansion of the CD4+ T cell population, per se, does not result in autoimmunity in adult mice. On the other hand, depletion of CD4+CD25+ T cells in 10-day-old euthymic mice resulted in a 30% incidence of autoimmune gastritis. These data suggest that CD4+CD25+ regulatory T cells may be important in protection against autoimmunity while the immune system is being established in young animals, but subsequently other factors are required to initiate autoimmunity.

Animals↗

PubMed1998

Dietary n-6 and n-3 fatty acids in immunity and autoimmune disease.

Clearly there is much evidence to show that under well-controlled laboratory and dietary conditions fatty acid intake can have profound effects on animal models of autoimmune disease. Studies in human autoimmune disease have been less dramatic; however, human trials have been subject to uncontrolled dietary and genetic backgrounds, infection and other environmental influences, and basic trial designs have been inadequate. The impact of dietary fatty acids on animal autoimmune disease models appears to depend on the animal model and the type and amount of fatty acids fed. Diets low in fat, essential fatty acid-deficient, or high in n-3 fatty acids from fish oils increase the survival and reduce disease severity in spontaneous autoantibody-mediated disease, whilst linoleic acid-rich diets appear to increase disease severity. In experimentally-induced T-cell-mediated autoimmune disease, essential fatty acid-deficient diets or diets supplemented with n-3 fatty acids appear to augment disease, whereas n-6 fatty acids prevent or reduce the severity. In contrast, in both T-cell and antibody-mediated auto-immune disease the desaturated and elongated metabolites of linoleic acid are protective. Suppression of autoantibody and T lymphocyte proliferation, apoptosis of autoreactive lymphocytes, and reduced pro-inflammatory cytokine production by high-dose fish oils are all likely mechanisms by which n-3 fatty acids ameliorate autoimmune disease. However, these could be undesirable long-term effects of high-dose fish oil which may compromise host immunity. The protective mechanism(s) of n-6 fatty acids in T-cell- mediated autoimmune disease are less clear, but may include dihomo-gamma-linolenic acid- and arachidonic acid-sensitive immunoregulatory circuits such as Th1 responses, TGF beta 1-mediated effects and Th3-like responses. It is often claimed that n-6 fatty acids promote autoimmune and inflammatory disease based on results obtained with linoleic acid only. It should be appreciated that linoleic acid does not reflect the functions of dihomo-gamma-linolenic and arachidonic acid, and that the endogenous rate of conversion of linoleic to arachidonic acid is slow (Hassam et al. 1975, 1977; Phylactos et al. 1994; Harbige et al. 1995). In addition to effects of dietary fatty acids on immunoregulation, inflammation as a consequence of immune activation in autoimmune disease may also be an important mechanism of action whereby dietary fatty acids modulate disease activity. In conclusion, regulation of gene expression, signal transduction pathways, production of eicosanoids and cytokines, and the action of antioxidant enzymes are all mechanisms by which dietary n-6 and n-3 fatty acids may exert effects on the immune system and autoimmune disease. Probably the most significant of these mechanisms in relation to our current understanding of immunoregulation and inflammation would appear to be via fatty acid effects on cytokines. The amount, type and balance of dietary fatty acids and associated antioxidant nutrients appear to impact on the immune system to produce immune-deviation or immunosuppressive effects, and to reduce immune-mediated inflammation which will in turn affect the susceptibility to, or severity of, autoimmune disease.

Animals↗