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PubMed1993

Autoantibodies against the human asialoglycoprotein receptor: effects of therapy in autoimmune and virus-induced chronic active hepatitis.

The hepatic asialoglycoprotein receptor (ASGPR) was recently identified as a target antigen for both humoral and cellular immune response in inflammatory liver diseases. Thereby anti-ASGPR autoantibodies directed against human substrate were closely associated with autoimmune chronic active hepatitis. The present study compares the occurrence, titer and immunoglobulin classification of anti-human(h-)-ASGPR antibodies in 23 patients with newly diagnosed autoimmune chronic hepatitis before and after initiation of immunosuppressive therapy to 22 patients with autoimmune hepatitis in remission. Additionally, 1-year follow-up examinations of 42 patients with HBsAg-positive chronic hepatitis and of 32 patients with chronic hepatitis C receiving recombinant interferon-alpha were included. Nineteen of 23 patients with newly diagnosed and 9/22 with autoimmune hepatitis in remission, 5/42 with untreated chronic hepatitis B and 5/32 patients with chronic hepatitis C exhibited anti-h-ASGPR at the beginning of the study. In autoimmune hepatitis anti-h-ASGPR were found in higher titers (median > 1:1000) than in viral hepatitis (maximum 1:400). After initiation of immunosuppressive therapy in autoimmune hepatitis anti-h-ASGPR decreased sharply. Eight of 19 patients eliminated anti-h-ASGPR within 18 months in contrast to 11 patients with persistent anti-h-ASGPR titer over 18 months and longer. Anti-h-ASGPR with maximum titer of 1:600 were detected in 5 patients with chronic hepatitis B (transiently in 4/5 patients) and in 2 patients with chronic hepatitis C during interferon-alpha. Anti-h-ASGPR were from immunoglobulin classes IgG and IgM in cases with untreated autoimmune hepatitis and chronic hepatitis B and C exhibiting mainly IgG2-subclass in autoimmune and IgG4 in viral hepatitis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1994

Prevalence of autoimmune diseases in the family members of patients with pemphigus vulgaris.

BACKGROUND: Several studies show that the family members of patients with autoimmune diseases are more susceptible to the development of the same or, more frequently, other autoimmune diseases. Although an association between pemphigus vulgaris (PV) and other autoimmune diseases has been reported, the presence of autoimmune diseases in the family members of patients with PV has not been studied. OBJECTIVE: The purpose of this study was to determine whether first-degree relatives of patients with PV are more susceptible to the development of autoimmune diseases. METHODS: A case-control study was done. A total of 830 first-degree relatives of 60 white patients with PV were compared with 890 relatives of 60 age-, race-, and sex-matched random controls. Both groups of relatives were screened for the presence of 16 autoimmune diseases. RESULTS: There was a highly significant increase in the prevalence of autoimmune diseases in the first-degree family members of PV patients, compared with controls. CONCLUSION: There is an increased susceptibility to the development of autoimmune diseases in the family members of patients with PV.

Adult↗

PubMed2000

Graft vs autoimmunity following allogeneic non-myeloablative blood stem cell transplantation in a patient with chronic myelogenous leukemia and severe systemic psoriasis and psoriatic polyarthritis.

OBJECTIVE: No specific therapy exists for autoimmune diseases caused by self-reactive lymphocytes. As shown in experimental animals, which led to pilot clinical studies, elimination of self-reactive lymphocytes can be accomplished with high-dose chemoradiotherapy, followed by autologous stem cell transplantation, by re-establishment of unresponsiveness to self antigens of newly generated lymphocytes, due to a mechanism of central clonal deletion. We hypothesized that self-reactive lymphocytes causing autoimmune disease may be successfully eliminated by highly immunosuppressive yet not necessarily myeloablative conditioning in conjunction with allogeneic blood stem cell transplantation, since immunocompetent alloreactive lymphocytes of donor origin can effectively eliminate residual host-type hematopoietic cells, self-reactive lymphocytes included, by a mechanism that resembles graft-vs-leukemia (GVL) effects. The present report is an attempt to confirm the existence of graft-vs-autoimmunity (GVA) effects in parallel with amplification of the alloreactive potential of donor lymphocytes following allogeneic non-myeloablative stem cell transplantation (NST). METHODS: We identified a patient with severe psoriatic arthritis who also had Philadelphia (bcr/abl) positive chronic myelogenous leukemia and therefore was fully eligible for NST. Both diseases responded initially to non-myeloablative conditioning involving fludarabine 30 mg/m2 x 6, anti-T-lymphocyte globulin 10 mg/kg X 4, and busulfan 4 mg/kg x 2. RESULTS: The initial NST procedure was uneventful and resulted in elimination of all signs of autoimmunity (psoriasis and arthritis). Recurrence of polyarthritis and exacerbation of psoriasis were observed in parallel with a significant increase in the proportion of male (host) DNA, and 5% of the mitoses were bcr/abl positive, indicating an increase in the clone of CML. Both bcr/abl-positive cells identified by RT-PCR and psoriatic arthritis were successfully eliminated following discontinuation of anti-GVHD prophylaxis with cyclosporine A (CSA), which resulted in activation of the alloreactive potential of donor T cells, accompanied by graft-vs-host disease (GVHD), suggesting the existence of GVA effects. RT-PCR for bcr/abl remains consistently negative for nearly 3 years, and all DNA remains donor type. CONCLUSIONS: The response of autoimmune disease manifestations to GVA effects in parallel with elimination of all host-derived hematopoietic cells supports our working hypothesis that autoimmune diseases caused by self-reactive lymphocytes may be effectively treated by elimination of alloreactive self-reactive lymphocytes following induction of host-vs-graft tolerance, in analogy with replacement of malignant or genetically abnormal host cells following DLI. It is therefore suggested that intentional GVA effects may be inducible by DLI following a conventional or preferably safer non-myeloablative regimen in recipients with life-threatening autoimmune diseases resistant to conventional modalities. Adoptive immunotherapy of autoimmunity may thus involve a two-step procedure: first, inducing host-vs-graft and graft-vs-host transplantation tolerance through a transient stage of mixed chimerism; second, inducing controlled GVA effects, initially by discontinuation of CSA and then, if indicated, by late outpatient DLI to eradicate residual hematopoietic cells of host origin.

Adult↗

PubMed2001

Treatment of autoimmune diseases by hematopoietic stem cell transplantation.

Remarkable advances have been made in bone marrow transplantation (BMT), which now has become a powerful strategy for the treatment of leukemia, aplastic anemia, congenital immunodeficiency disorders, and autoimmune diseases. Using various animal models, allogeneic BMT has been found to be useful in the treatment of autoimmune diseases. In MRL/lpr mice, which are radiosensitive (<8.5 Gy) and are an animal model for autoimmune disorders, conventional BMT resulted in only transient effects; the manifestations of the autoimmune diseases recurred 3 months after BMT. However, the combination of BMT plus bone grafts (to recruit donor stromal cells) was capable of preventing the recurrence of autoimmune diseases in MRL/lpr mice. This strategy was found to be ineffective in the treatment of MRL/lpr mice that had developed autoimmune diseases, because these mice were more sensitive to the effects of radiation after the onset of lupus nephritis due to uremic enterocolitis. We have recently discovered a safer strategy for treatment of autoimmune diseases, which includes fractionated irradiation (5.5 Gy x 2) (day -1) followed by portal venous injection (day 0) plus intravenous injection (day 5) of donor unfractionated bone marrow cells. We successfully treated autoimmune diseases in MRL/lpr mice using this strategy; 100% of MRL/lpr mice treated in this fashion survive >1 year after treatment. We identified the mechanisms underlying the components of this approach and have found that stromal cells play a crucial role in successful BMT. In this review, the conditions essential for successful allogeneic BMT are discussed.

Animals↗

PubMed2002

Female MRL.MpJ-Fas(lpr) autoimmune mice have greater hearing loss than males.

Although women make up approximately 60-70% of the patients with autoimmune hearing loss, little is known about the impact of gender on this cochlear disease. To explore this relationship of gender and autoimmune inner ear disease, an evaluation was made of cochlear function in male and female autoimmune MRL.MpJ-Fas(lpr) mice. Autoimmune disease and hearing loss onset occur at 3-4 months of age, so mice were tested with auditory brainstem response audiometry at 3, 6, and 9 months of age to identify potential gender differences in thresholds. Sera also were analyzed for differences in the autoimmune factors of immune complexes, anti-nuclear antibodies, and hematocrits. By 9 months of age the surviving mice showed a dramatic gender difference. Female mice had thresholds 25-45 dB higher than males at 4, 8, and 16 kHz, although male thresholds at 32 kHz had risen sufficiently to be statistically similar to those for females. No gender differences were seen in any of the systemic autoimmune factors. These findings of worse hearing in female autoimmune mice parallel a reported female preponderance in clinical immune hearing disorders. This potential gender influence in autoimmune inner ear disease must be better understood for effective evaluation and treatment of this disorder.

Animals↗

PubMed2005

Is idiopathic chronic pancreatitis an autoimmune disease?

BACKGROUND & AIMS: The proportion of patients with idiopathic chronic pancreatitis (ICP) that have an autoimmune origin is unknown. Three forms of ICP have been described: pseudotumoral, duct-destructive, and usual chronic pancreatitis. The aim of this study was to identify autoimmune stigmata in the 3 forms. METHODS: All patients who underwent exploration for ICP were included. The following data were recorded: examination by an internal medicine specialist, autoantibodies and immunoglobulin screening, and pancreatic duct imaging. RESULTS: Sixty patients were included (pseudotumoral, n = 11; duct-destructive, n = 27; usual, n = 22). There were no significant differences among the 3 types with regard to sex ratio, age, frequency of acute pancreatitis, or obstructive jaundice. Pancreatic calcifications were seen only in the usual form (81%; P = .0001). Autoimmune disease was present in 10 patients: ulcerative colitis in 5 patients, primary sclerosing cholangitis in 2 patients, and Sjögren's syndrome, Hashimoto's thyroiditis, and Graves' disease in 1 patient each. Autoimmune diseases were not more frequent in patients with pseudotumoral (36%) or duct-destructive (19%) forms than in those with the usual form (5%, P = .06). Immunoglobulin G4 levels were increased in 2 of 6 in the pseudotumoral, 1 of 9 in the duct-destructive, and 0 of 12 patients in the usual group. Combining clinical and biochemical autoimmune parameters, 24 patients (40%) had at least 1 autoimmune marker or disease. CONCLUSIONS: Clinical or biochemical autoimmune stigmata are present in 40% of patients with ICP. Autoimmune mechanisms may be frequent in idiopathic pancreatitis.

Adolescent↗

PubMed2001

Estrogen, prolactin, and autoimmunity: actions and interactions.

Estrogen and prolactin have a reciprocal endocrinologic relationship and both hormones have pleiotropic effects on the immune system. Despite the presence of a number of confounding variables, these hormones modulate autoimmunity; however, mechanisms by which this modulation occurs remain obscure. Estrogen appears to suppress cell-mediated and augment humoral-based immunity. Prolactin appears to stimulate both cell and humoral-based immunity. Both hormones have been shown to modulate IFN gamma secretion. Similar evidence in experimental models, human autoimmune disease, and during pregnancy in autoimmune disease patients suggests disparate effects of estrogen and prolactin on autoimmune responses and disease pathogenesis. In the NZB x NZW F1 mouse model of lupus, prolactin accelerates disease expression, whereas estrogen, devoid of its prolactin stimulating properties, is immunosuppressive and inhibits IL-2 production. Estrogen, because of its endocrinologic and immune effects, may directly or indirectly stimulate or inhibit immune responses. These dichotomous effects have limited its successful pharmacologic manipulation in human autoimmune disease with estrogen compounds, tamoxifen, oral contraceptives, antigonadotropic agents, or ovulation induction regimens. In contrast, reduction of immunostimulatory concentrations of prolactin with bromocriptine has successfully suppressed development or expression of murine and human autoimmune disease. Further investigation into actions and interactions of estrogen and prolactin with autoimmunity will provide a better understanding of the female preponderance of autoimmunity and facilitate a more rational approach to hormonal immunotherapy.

Animals↗

PubMed2002

[Autoimmune hepatitis and overlap syndrome: diagnosis].

Autoimmune hepatitis (AIH) is a rare autoimmune disease (incidence about 5% among all chronic liver disorders) that reflects a loss of tolerance to normal hepatic proteins. AIH is characterized by female preponderance, hypergammaglobulinemia, extrahepatic syndromes and a good response to immunosuppressive treatment. AIH may be subdivided into two or three subtypes. AIH type 1 is characterized by antinuclear autoantibodies (ANA) and/or smooth muscle antibodies (SMA). SMA are actin-specific, can occur without ANA and their presence relates strongly to AIH. AIH type 2 is defined by the presence of anti-liver-kidney microsomal antibodies (LKM-1). Patients with AIH type 2 are typically younger at the time of disease onset, exhibit higher inflammatory activity, suffer more frequent relapses under immunosuppressive treatment and are more likely to progress to cirrhosis. AIH type 3 is characterized by autoantibodies against the soluble liver antigen (SLA) and liver-pancreas antigen (LP), but ANA/SMA are frequently present and, therefore, some authors consider this autoantibody manifestation as belonging to AIH type 1. Antineutrophil cytoplasmic antibodies (ANCA) recognize cytoplasmic or nuclear components of neutrophilic granulocytes and are detected with high prevalence in patients with autoimmune liver diseases. They are associated with AIH type 1 but not with AIH type 2. However, 40-70% of patients with primary sclerosing cholangitis (PSC) also produce these autoantibodies. Autoimmune cholangitis is an idiopathic disorder with mixed hepatocellular and cholestatic findings that typically has antinuclear antibodies (ANA). It may be considered as an atypical form of primary biliary cirrhosis. It has been recognized that some forms of AIH may also occur with variable incidence and severity especially in patients with primary biliary cirrhosis (overlap AIH/PBC) or primary sclerosing cholangitis (AIH/PSC). On the basis of clinical, biochemical, serological, histological and radiological criteria a clear distinction between these conditions can be readily made in the majority of cases. An association of AIH-typical autoantibodies (anti-LKM-1, anti-SLA/LP) in association with antimitochondrial autoantibodies (AMA) almost confirm the overlap syndrome AIH/PBC. In PSC patients expressing typical ERCP findings and suffering from inflammatory bowel disease (IBD), the diagnosis of an overlap syndrome between PSC/AIH can be readily made in the presence of ANCA and AIH relevant autoantibodies. Apart from this kind of overlap syndrome involving different types of autoimmune disorders within the liver AIH can be also associated with other organspecific autoimmune disorders as documented in the autoimmune polyglandular syndrome type 1 (APS-1). In this disease homozygosity for a defect in a single gene (AIRE) leads to a broad spectrum of organ specific autoimmune diseases.

Autoantibodies↗

PubMed1997

A CTLA-4 gene polymorphism is associated with both Graves disease and autoimmune hypothyroidism.

OBJECTIVE: The autoimmune thyroid diseases, Graves disease and autoimmune hypothyroidism, result from a complex interaction between genetic, environmental and endogenous factors. The genetic loci conferring susceptibility remain unclear. A recent report has demonstrated an association between a microsatellite polymorphism of the CTLA-4 gene (allele 106) on chromosome 2q33 and Graves' disease in Caucasian patients in the USA. The aim of the present study was to confirm this association in UK patients and to determine whether this polymorphism is also associated with autoimmune hypothyroidism. DESIGN: Analysis of Caucasian patients with autoimmune thyroid disease from a single clinic, compared to local Caucasian controls. PATIENTS: We studied 112 patients with Graves' disease, 44 with autoimmune hypothyroidism and 91 controls. MEASUREMENTS: CTLA-4 microsatellite gene polymorphisms were determined by polymerase chain reaction amplification of genomic DNA and resolution of the products on sequencing gels. RESULTS: As in previous studies, 21 alleles of the CTLA-4 microsatellite region were detected. Allele 106 was significantly increased in patients with Graves' disease (P = 0.006) and in those with autoimmune hypothyroidism (P = 0.02) when compared to controls. There was no significant difference between the groups in the distribution of the other alleles and no association between allele 106 and sex, HLA-DR or -DQ specificities or the presence of ophthalmopathy in the Graves' patients. CONCLUSIONS: These results confirm that the CTLA-4 gene, or one closely associated with it, confers susceptibility to Grave's disease but is not specific as the CTLA-4 106 allele is also associated with autoimmune hypothyroidism. This association seems to be with autoimmune thyroid disease in general.

Abatacept↗

PubMed2000

Localization and characterization of antigen-presenting dendritic cells in the gastric mucosa of murine and human autoimmune gastritis.

BACKGROUND: Activated CD4+ T cells and inflammatory cytokines are implicated in the pathogenesis of experimental autoimmune gastritis. However, there is a paucity of information about the cells that induce them. Antigen-presenting dendritic cells (DCs) play a cardinal role in the formation and survival of activated lymphocytes. MATERIALS AND METHODS: Autoimmune gastritis was induced in neonatal BALB/c mice by thymectomy. DCs were detected in situ in the gastric mucosa from thymectomized mice and in patients with autoimmune gastritis, by immunohistochemistry and immunoelectron microscopy. The expression of MHC class II and CD86 antigens on DCs in the gastric mucosa and spleen was evaluated in dual-colour flow cytometry. RESULTS: DCs were detected in the gastric mucosa of mice with autoimmune gastritis, and the number of DCs increased as the levels of gastritis became more severe as time passed following thymectomy. Flow cytometric analyses revealed that more than 60% of the DCs in the gastric mucosa had a mature phenotype (expressed MHC class II and/or CD86 antigens) both at 4 and 16 weeks after thymectomy. Activated and mature DCs were localized in the gastric mucosa from patients with autoimmune gastritis. CONCLUSIONS: This is the first report on the localization and phenotypes of DCs in the gastric mucosa of autoimmune gastritis. The presence of mature DCs in the gastric mucosa of murine and human autoimmune gastritis, in spite of their absence in the gastric mucosa of normal mice, suggests that mature DCs play a role in the pathogenesis of autoimmune gastritis.

Animals↗

PubMed1999

Effect of ursodeoxycholic acid on autoimmune-associated chronic hepatitis C.

BACKGROUND: Hypergammaglobulinaemia and various auto-antibodies which are commonly seen in autoimmune hepatitis are also found in patients with chronic hepatitis C. We recently reported that ursodeoxycholic acid (UDCA) improved liver function tests and immunoserological markers in patients with type I autoimmune hepatitis. The aim of this study was to prospectively evaluate the efficacy of UDCA on autoimmune-associated chronic hepatitis C. METHODS: Immunoglobulin G (IgG), anti-nuclear antibodies (ANA) and anti-smooth muscle antibodies (ASMA) were determined in 95 patients with chronic hepatitis C. All patients were positive for hepatitis C virus RNA. Autoimmune-associated chronic hepatitis C (C-AIH) was defined by elevated serum IgG level (> or = 2.0 g/dL) and high titres of ANA and/or ASMA (> or = 1 : 160). Nine (9%) of 95 patients were diagnosed as C-AIH. All the C-AIH patients and 30 of the remaining 86 chronic hepatitis C patients without autoimmune features (CHC) were treated with UDCA (600 mg/day) for 1 year. RESULTS: Autoimmune-associated chronic hepatitis C patients included one man and eight women and their AIH scores, as defined by the International Autoimmune Hepatitis Group, were significantly higher than the CHC patients. Before UDCA therapy, there were no significant differences in aspartate aminotransferase (AST), alanine aminotransferase (ALT) and y-glutamyl transpeptidase (gamma-GTP) levels between C-AIH and CHC patients. However, after 1 year UDCA therapy, AST, ALT and gamma-GTP were significantly lower in C-AIH patients (P< 0.05) than in CHC patients. In C-AIH, ANA titres in seven of nine patients and ASMA titres in five of seven patients were reduced after 1 year UDCA treatment. CONCLUSIONS: These results suggest that UDCA is a useful therapeutic agent for autoimmune-associated chronic hepatitis C.

Alanine Transaminase↗

PubMed2000

Anti-neutrophil cytoplasmic antibodies in patients with chronic liver diseases: prevalence, antigen specificity and predictive value for diagnosis of autoimmune liver disease. Swedish Internal Medicine Liver Club (SILK)

BACKGROUND: Anti-neutrophil cytoplasmic antibodies (ANCA) against proteinase 3 are diagnostic of Wegener's granulomatosis, but ANCA occur also in patients with other inflammatory disorders, such as ulcerative colitis, primary sclerosing cholangitis (PSC) and autoimmune hepatitis. As their predictive value for autoimmune liver disease remains unknown, we analysed the prevalence and antigen specificity of ANCA in patients with various chronic liver diseases (CLD). METHODS: We studied sera from 100 patients with primary biliary cirrhosis (PBC), from 76 with PSC and from 279 with various CLD, consecutively drawn during a 5-year period at the time of liver biopsy. The ANCA were detected by indirect immunofluorescence (IIF) while the antigen specificity was characterized by ELISA by using lactoferrin, neutrophil elastase, cathepsin G and BPI (bactericidal/permeability increasing protein) as antigens. RESULTS: In PBC, ANCA were detected by IIF in 39 patients (39%). The antigen reactivity by ELISA was lactoferrin in seven, elastase in 15, BPI in 20 and cathepsin G in four patients. Four patients had reactivity against more than one antigen. In PSC, IIF demonstrated ANCA in 49 patients (65%). The antigen reactivity was lactoferrin in 17, elastase in 14, BPI in 20 and cathepsin G in four patients. Twelve patients showed reactivity against more than one antigen. In CLD, ANCA were observed in sera from 55 patients (20%). Nineteen of 45 patients (42%) with autoimmune liver disease were ANCA positive versus 36/234 (15%) with non-autoimmune liver disease (P = 0.0002). Among IIF-positive patients, antibody reactivity against lactoferrin was noted in 14, elastase in 28, BPI in 25 and cathepsin G in five patients. Twenty-one patients had reactivity against more than one antigen. Elastase and BPI antibodies occurred more frequently in patients with autoimmune compared to non-autoimmune liver disease (P < 0.01). CONCLUSIONS: Anti-neutrophil cytoplasmic antibodies are prevalent in patients with chronic liver diseases, but although they occur more frequently in patients with autoimmune liver disease their specificity and sensitivity for autoimmune liver disease is low. The predominant antigens are lactoferrin, elastase and BPI, but the correlation between IIF findings and ELISA reactivity against these antigens is weak.

Antibodies, Antineutrophil Cytoplasmic↗

PubMed2002

Is coeliac disease more prevalent in young adults with coexisting Type 1 diabetes mellitus and autoimmune thyroid disease compared with those with Type 1 diabetes mellitus alone?

AIM: It is known that patients with Type 1 diabetes mellitus are more prone to develop coeliac disease and that autoimmune thyroid disease occurs more frequently in patients with coeliac disease. We therefore assessed whether coeliac disease, either known or occult, occurs more frequently in young/middle aged adults with Type 1 diabetes and coexisting autoimmune thyroid dysfunction than in adults with Type 1 diabetes alone. METHODS: The prevalence of known coeliac disease was assessed in 509 (301 males, aged 16-55 years) patients with Type 1 diabetes, 28 (5.5%) of whom had treated autoimmune thyroid disease. In a second study 38 patients with Type 1 diabetes and coexisting autoimmune thyroid disease along with 112 patients with Type 1 diabetes alone were then screened for coeliac disease using serum IgA endomysial antibodies and IgA gliadin antibodies. RESULTS: Seven of the 509 patients (1.4%) had been diagnosed with coeliac disease and two of these had later developed autoimmune thyroid disease (both hypothyroid). The subsequent screening exercise found that one of the 38 patients with both Type 1 diabetes and thyroid disease had positive endomysial antibodies on screening. However, duodenal biopsy was negative for coeliac disease. There were two patients with positive endomysial antibodies in the group of 112 patients with diabetes only. Both had duodenal biopsy but only one was consistent with coeliac disease. CONCLUSION: The prevalence of known coeliac disease in this young adult Type 1 diabetes clinic in North-west England was 7/509 (1.4%). Two of these seven patients with coeliac disease were from the group of 28 who had autoimmune thyroid disease as well. Therefore we suggest that patients with known coeliac disease and Type 1 diabetes should be screened for autoimmune thyroid disease. The second screening study then found 3/150 (2%) to have a serological marker for coeliac disease. However, patients with both Type 1 diabetes and autoimmune thyroid disease were not more likely to have occult coeliac disease compared with those with Type 1 diabetes only.

Adolescent↗

PubMed1998

Epitope spreading: lessons from autoimmune skin diseases.

Autoimmune diseases are initiated when patients develop aberrant T and/or B cell responses against self proteins. These responses presumably are directed to single immunogenic epitopes on these proteins. Recent data in animal models of autoimmune diseases suggest that the targets of immune responses in autoimmunity do not remain fixed, but can be extended to include other epitopes on the same protein or other proteins in the same tissue, a phenomenon termed "epitope spreading." The "epitope spreading" phenomenon also applies to situations in which tissue damage from a primary inflammatory process causes the release and exposure of a previously "sequestered" antigen, leading to a secondary autoimmune response against the newly released antigen. In experimental autoimmune animal diseases, "epitope spreading" seems to have significant physiologic importance in determining the course and duration of disease. In this paper, we review the current concepts in animal models of autoimmune diseases in order to define the "epitope spreading" phenomenon, and we then propose how this phenomenon might play a significant role in the development and the course of autoimmune skin diseases. Hopefully, an understanding of "epitope spreading" will help the dermatology community to better understand the pathogenesis of autoimmune skin diseases and to rationally fashion disease-specific immune therapy in the future.

Animals↗

PubMed2002

Serum monocyte chemoattractant protein-1 is increased in chronic autoimmune thyroiditis.

Chemokines are a large family of cytokines, which may be involved in the pathogenesis of a wide variety of inflammatory or autoimmune conditions. The role of chemokines in chronic autoimmune thyroiditis is unknown. We sought to examine the role of CC chemokines in chronic autoimmune thyroiditis. We measured serum levels of CC chemokines, including monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein 1a and 1b (MIP-1a and MIP-1b) in 32 women with chronic autoimmune thyroiditis in comparison with 2 control groups (33 apparently healthy women and 43 women with benign cold thyroid nodules) by enzyme-linked immunosorbent assay (ELISA). We found a 45% increase in serum MCP-1 levels in women with chronic autoimmune thyroiditis compared with either of the 2 control groups (P =.01). There was no difference in either serum MIP-1a (P =.69) or MIP-1b (P =.81) levels between women with chronic autoimmune thyroiditis and controls. Among women with chronic autoimmune thyroiditis, women with a family history of hypothyroidism had a 59% increase in serum MCP-1 levels compared with women with no family history of hypothyroidism (P =.02). Serum MCP-1 levels were associated with serum levels of antithyroid peroxidase (r =.2, P =.03) (anti-TPO Ab) and antithyroglobulin (r =.2, P =.04) antibodies (anti-TG Ab). There was no association between serum MCP-1 levels and serum free thyroxine index (P =.57), triiodothyronine (T(3)) (P =.47) or thyroid-stimulating hormone (TSH) (P =.47) levels. Serum MCP-1 is increased in women with chronic autoimmune thyroiditis, especially in the presence of a family history of hypothyroidism, indicating a possible pathogenetic role for MCP-1 in this condition.

Adult↗

PubMed1985

Rationale for bone marrow transplantation in the treatment of autoimmune diseases.

Transplantation of normal bone marrow from C3H/HeN nu/nu (H-2k) mice into young MRL/MP-lpr/lpr (MRL/l; H-2k) mice (less than 1.5 mo) prevented the development of autoimmune diseases and characteristic thymic abnormalities in the recipient mice. When female MRL/1 (greater than 2 mo) or male BXSB (H-2b) mice (9 mo) with autoimmune diseases and lymphadenopathy were lethally irradiated and then reconstituted with allogeneic bone marrow cells from young BALB/c nu/nu (H-2d) mice (less than 2 mo), the recipients survived for more than 3 mo after the bone marrow transplantation and showed no graft-versus-host reaction. Histopathological study revealed that lymphadenopathy disappeared and that all evidence of autoimmune disease either was prevented from developing or was completely corrected even after its development in such mice. All abnormal T-cell functions were restored to normal. The newly developed T cells were found to be tolerant of both bone marrow donor-type (BALB/c) and host-type (MRL/1 or BXSB) major histocompatibility complex (MHC) determinants. Therefore, T-cell dysfunction in autoimmune-prone mice can be associated with both the involutionary changes that occur in the thymus of the autoimmune-prone mice and also to abnormalities that reside in the stem cells. However, normal stem cells from BALB/c nu/nu donors can differentiate into normal functional T cells even in mice whose thymus had undergone considerable involution, as in the case of BXSB or MRL/1 mice in the present studies. These findings suggest that marrow transplantation may be a strategy ultimately to be considered as an approach to treatment of life-threatening autoimmune diseases in humans. T-cell dysfunction in autoimmune-prone mice previously attributed to involutionary changes that occur in the thymus of these mice may instead be attributed to abnormalities that basically reside in the stem cells of the autoimmune-prone mice.

Animals↗

PubMed1992

Expression of myosin-class II major histocompatibility complexes in the normal myocardium occurs before induction of autoimmune myocarditis.

Determining how an autoimmune response is initiated is essential to understanding the mechanisms of autoimmunity. Self-reactive T cells, self-protein, and a failure of tolerance to that self-protein are all involved in the pathogenesis of autoimmune disease; yet it is not clear how self-reactive T cells find the target self-protein to initiate an autoimmune response. Although a variety of self-proteins have been shown to be presented on both class I and class II major histocompatibility complex (MHC) molecules, the relationship of these self-proteins to autoimmune disease has not been established. To explore this further, we generated a T-cell hybridoma that recognizes mouse cardiac myosin, the self-protein that induces murine autoimmune myocarditis. Using this hybridoma as a probe to detect myosin-class II MHC complexes, we isolated a class II MHC+/CD45+ residential antigen-presenting cell (APC) population directly from the hearts of normal mice and looked for evidence of endogenous processing of cardiac myosin by these APC. In this report we show that myosin-class II MHC complexes are found on residential APC in the normal mouse heart. Induction of autoimmune myocarditis increased the expression of myosin-class II MHC in the heart and enhanced their APC functions. This result is a direct demonstration that epitopes of a self-antigen involved in initiating an autoimmune disease are endogenously processed and presented within the target organ.

Animals↗

PubMed1997

Prevention of development of autoimmune disease in BXSB mice by mixed bone marrow transplantation.

Transplantations of fully allogeneic, autoimmune-resistant T-cell-depleted marrow (TCDM) plus syngeneic, autoimmune-prone TCDM into lethally irradiated BXSB mice were carried out to investigate the ability of the mixed bone marrow transplantation (BMT) to prevent development of autoimmune disease and, at the same time, to reconstitute fully the immunity functions of heavily irradiated BXSB recipients. Male BXSB mice were engrafted with mixed TCDM from both allogeneic, autoimmune-resistant BALB/c mice and syngeneic, autoimmune-prone BXSB mice. BMT with mixed TCDM from both resistant and susceptible strains of mice (mixed BMT) prolonged the median life span and inhibited development of glomerulonephritis in BXSB mice. BMT with mixed TCDM also prevented the formation of anti-DNA antibodies that is typically observed in male mice of this strain. Moreover, mixed BMT reconstituted primary antibody production in BXSB recipients, so that no annoying immunodeficiencies that are regularly observed in fully allogeneic chimeras were present in the recipient of the mixed TCDM. These findings indicate that transplanting allogeneic, autoimmune-resistant TCDM plus syngeneic, autoimmune-prone TCDM into lethally irradiated BXSB mice prevents development of autoimmune disease in this strain of mice. In addition, this dual BMT reconstitutes the immunity functions and avoids the immunodeficiencies that occur regularly in fully allogeneic chimeras after total-body irradiation.

Animals↗