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PubMed2005

Advances in the treatment of autoimmune diseases; cellular activity, type-1/type-2 cytokine secretion patterns and their modulation by therapeutic peptides.

Autoimmune diseases are many, have an overall prevalence of about 3% of the world population, affecting more women than men, and their incidence is influenced by genetics and the environment. It is currently thought that the immune response of a genetically predisposed individual to an environmental pathogen, under the influence of inadequate or non-functional immunoregulatory mechanisms, can lead to the development of an autoimmune disease. Advances in the treatment of autoimmune diseases follow a better understanding of the abnormalities in the cellular activity pathways and the resulting, often permanent, imbalance of the pro- and anti-inflammatory cytokine expression profiles. Over the past few years, there has been a dramatic change in the therapeutic regimens employed in autoimmune diseases, with soluble receptors, monoclonal antibodies and molecular mimetics enhancing or gradually replacing conventional immunosuppressive therapies. New biologicals have been developed, targeting defined pathways of the adaptive immune response. One approach towards the therapeutic management of autoimmune diseases involves the design and use of peptide analogs of disease-associated epitopes to be used as immunomodulatory drugs. Peptides can target cell-functions directly, by interfering with the formation of the tri-molecular complex MHC-Peptide-TCR, and/or they can target soluble mediators such as cytokines or their receptors, eventually replacing monoclonal antibody therapies. This review offers an update on the treatment modalities of certain prototypic autoimmune diseases, based on the current knowledge of disease pathogenesis, with emphasis on cell activation and cytokine expression profiles.

Arthritis, Rheumatoid↗

PubMed2006

Targeting cytokines of the interleukin-12 family in autoimmunity.

In the past, autoimmunity was thought to be mediated by antibodies and immune complexes. It has now become clear that many autoimmune diseases, especially tissue specific, are T cell-mediated, or at least T cell-dependent. The pathogenesis of cell-mediated autoimmune diseases, including multiple sclerosis, uveitis, diabetes, arthritis, and others, is now thought to be, in a large measure, driven by interferon-gamma-producing, antigen-specific T cells, which are polarized toward the T helper type 1 (Th1) phenotype. Interleukin (IL)-12 and the more recently discovered IL-23 and IL-27 constitute a unique family of structurally-related, heterodimeric cytokines, which regulate cell-mediated immune responses and Th1-type inflammatory reactions. Thus, these cytokines may have a central role in the development and progression of cell-mediated autoimmune diseases. Therefore, pharmacologically targeting cytokines of the IL-12 family would be useful in the modulation of several autoimmune diseases. This review summarizes the recent findings concerning IL-12 family cytokine-mediated autoreactive inflammatory responses, and also describes some possible therapeutic interventions, including medicinal compounds at mitigating autoimmune inflammation.

Animals↗

PubMedDate not supplied

[Psoriasis and autoimmune skin disorders].

INTRODUCTION: Presuming that psoriasis is an autoimmune skin disease, the aim of this study was to establish its association with other autoimmune skin diseases. The material was obtained at the Dermatovenereological Clinic--Clinical Center Novi Sad. MATERIAL AND METHODS: This 10-year retrospective study (1990-1999) included 1743 psoriasis patients. The control group consisted of 7492 nonpsoriatic dermatological patients. RESULTS: Association of psoriasis with other dermatological diseases of autoimmune nature has been established in 13 (0.74%) patients. The most frequent association was with lichen ruber planus in five patients, with alopecia areata and vitiligo in three patients, and in one with bullous pemphigoid and herpetiform dermatitis. Using Fisher's test no significant association was established. DISCUSSION AND CONCLUSION: According to literature data association of psoriasis with other autoimmune diseases is well known, but rare, which is in accordance with our results. The question arises whether this association is the matter of poor coexistence or the matter of genetic mutations. However, once established, these associations can further highlight the autoimmune nature of psoriasis. The research of autoimmunity would lead us to epithelial cells in thymus, and their badly learnt cognitive function about what is own, and what is not.

Autoimmune Diseases↗

PubMedDate not supplied

[A histologic variant of autoimmune hepatitis with zonal necrosis].

Autoimmune hepatitis type 1 in a 8-year old girl is described. The diagnosis was established using International Autoimmune hepatitis group scoring system. In addition to characteristic histologic features of autoimmune hepatitis (periportal hepatitis, piecemeal necrosis and rozettes) prominent centrilobular necrosis was discovered. As an isolate finding in autoimmune hepatitis, this type was described only in five cases. In our unique case centrilobular necrosis is a very important parallel finding previously not detected in autoimmune hepatitis. Some experimental studies suggest that cytocins present in inflammatory cell infiltrate in the liver play a pathologic role in autoimmune liver cell damage.

Child↗

PubMedDate not supplied

Thyroid autoimmunity in chronic urticaria.

A subset of patients with idiopathic chronic urticaria (CU) has been recently classified as autoimmune on the basis of two main findings: association with thyroid autoimmunity and with anti-IgE and/or anti-IgE receptor antibodies. The association of CU with thyroid autoimmunity has been known since 1983, but its frequency varies in different reports. The objective of the present study was to verify the prevalence of thyroid antibodies (anti-thyroid peroxidase, TPO; thyroglobulin, TG; TSH-receptor, TSH-R) in two distinct series of CU: of known cause (70 cases, group A) and idiopathic (52 cases, group B). Twenty-three patients (M/F:7/16) of group A (33%) and 12 (M/F:4/8) of group B (23%) tested positive for at least one type of thyroid antibody. The difference was not statistically significant. Thyroid disease or altered serum TSH levels (requiring treatment) were present in 39% of group A and 42% of group B seropositive patients. In conclusion, the present study shows that CU, either of known cause or idiopathic, is more common in females than in males and is significantly associated with thyroid autoimmunity. These results were not expected on the assumption that autoimmune phenomena are a specific pattern of idiopathic CU. Thus, screening for thyroid autoimmunity and function is advisable in all patients with CU for the early identification of patients requiring either treatment of underlying thyroid dysfunction or follow-up.

Adolescent↗

PubMed1994

Asialoglycoprotein receptor function of hepatocytes in patients with autoimmune hepatitis.

To assess whether the hepatocyte asialoglycoprotein receptors are affected in patients with autoimmune hepatitis, the function of the hepatocyte asialoglycoprotein receptor was investigated in patients with autoimmune hepatitis or chronic hepatitis C. A new radionuclide liver imaging technique, Technetium-99m diethylenetriamine-pentaacetic acid-galactosyl human serum albumin, was applied to evaluate the function of the receptor. A Receptor Index (LHL 15) was calculated by dividing the radioactivity of the liver region-of-interest (ROI) by that of the liver plus heart ROI 15 min after radiolabeled ligand injection. Serum albumin, prothrombin time, hepaplastin test and plasma retention rate of indocyanine green at 15 min were not significantly different between patients in the autoimmune hepatitis group and chronic hepatitis C group. In addition, the Receptor Index of patients with autoimmune hepatitis, in whom the asialoglycoprotein receptor is a candidate target antigen for autoimmune response, was similar to that of patients with chronic hepatitis C. These results indicate that the hepatocyte receptor for asialoglycoproteins is not affected in patients with autoimmune hepatitis.

Adult↗

PubMed1997

Absence of LKM-1 antibody reactivity in autoimmune and hepatitis-C-related chronic liver disease in Sweden. Swedish Internal Medicine Liver club.

BACKGROUND: Type-2 autoimmune hepatitis is a subgroup of chronic hepatitis characterized by the presence of liver/kidney microsomal autoantibodies type 1 (LKM-1). A frequent association with chronic hepatitis C suggests that hepatitis virus might trigger autoimmune reactivity. LKM-1-positive chronic hepatitis is not uncommon in southern Europe but is rarely seen in the USA and the UK. The prevalence in Scandinavia is hitherto unknown. METHODS: We used an automated prototype LKM-1 immunometry-based assay (IMx) to detect LKM-1 antibodies in sera from 350 Swedish patients with chronic liver diseases (100 with primary biliary cirrhosis, 80 with primary sclerosing cholangitis, 100 with hepatitis C, and 70 patients with various forms of chronic hepatitis, including 36 autoimmune cases), and from 17 children with autoimmune hepatitis. Sera reactive in the IMx assay were subjected to immunofluorescence testing. RESULTS: No clearly LKM-reactive sera were detected. Serum samples from 29 patients were borderline reactive in the IMx assay but tested negative in the confirmatory immunofluorescence test. Positive tests in the former assay were likely caused by reactivity against microsomal antigens other than LKM-1/cytochrome P450IID6. CONCLUSIONS: LKM-1-positive type-2 autoimmune hepatitis is very rare in Sweden. Furthermore, chronic hepatitis C did not trigger this type of autoimmune reactivity in our patients, probably owing to genetic insusceptibility.

Adolescent↗

PubMed1997

Disease-associated autoimmunity and prevention of insulin-dependent diabetes mellitus.

Insulin-dependent diabetes mellitus (IDDM) is a chronic autoimmune disease with a subclinical prodromal period characterized by selective destruction of insulin-producing beta cells in the pancreatic islets. This process is assumed to be T-cell mediated, but the emergence of disease-associated autoantibodies into the peripheral circulation is usually the first noticeable sign of beta-cell autoimmunity in human IDDM. Recent observations have suggested that beta-cell autoimmunity may be induced in any individual at any time. There are also data indicating that such autoimmunity may have been initiated prenatally in some individuals. Only a proportion of those with signs of islet cell autoimmunity progress to clinical disease, and harmless beta-cell autoimmunity reflected by positivity for a single autoantibody specificity seems to appear without any relation to genetic IDDM susceptibility. One can hypothesize that in most subjects HLA-conferred protection against IDDM prevents the beta-cell process from progressing to a stage of destructive insulitis that may lead to clinical disease. Environmental factors may trigger initial beta-cell damage and subsequently accelerate the destructive process. Non-HLA genes may also be involved in the regulation of the progression rate. Prospective observations of prediabetic individuals have revealed that IDDM-associated autoantibodies tend to appear sequentially, and that those who progress to clinical disease mount a strong humoral immune response to most known disease-associated antigens. This indicates that the immune response associated with beta-cell destruction is not purely T-helper 1 biased. Antigen-specific immunotherapy may in the future offer effective measures to intervene in preclinical IDDM to prevent end-stage insulitis. Substantially more data have to be generated, however, on the mechanisms, efficacy and safety of such therapy before it is possible to judge its clinical applicability.

Autoimmunity↗

PubMed1993

Induction of experimental autoimmune myasthenia gravis with acetylcholine receptors using a nonionic block copolymer as adjuvant.

To induce autoimmune diseases in animals, the auto-antigen has to be emulsified in adjuvants (e.g., complete Freund's adjuvant) containing microbial products such as Mycobacterium tuberculosis. But these powerful immunoadjuvants are not without undesirable immune response to the microbial proteins and induction of adjuvant arthritis, which could interfere with the antigen specific autoimmune response to be tested. This study was performed to evaluate the requirement of microbial products in the induction of experimental autoimmune diseases, and to identify an adjuvant without unwanted immune responses. C57BL/6 mice were inoculated with Torpedo acetylcholine receptors (T-AChR) emulsified in Titermax (TM), an adjuvant containing nonionic block copolymer and no microbial products, and evaluated for experimental autoimmune myasthenia gravis (EAMG) susceptibility. Mice immunized with T-AChR in TM demonstrated characteristic myasthenic muscle weakness with electrophysiological defect, elevated serum anti-AChR antibodies, and muscle AChR loss. None of the mice that received TM alone had muscle weakness, serum anti-AChR antibodies or muscle AChR loss. The data imply that microbial products are not critical in the induction of autoimmune diseases like myasthenia gravis in mice. Further, nonionic block copolymer could be an ideal adjuvant in the induction of autoimmune diseases in animals.

Adjuvants, Immunologic↗

PubMed2000

Neonatal tolerant immunity for vaccination against autoimmunity.

Autoimmunity arises when the immune system no longer tolerates self and precipitates lymphocyte reactivity against our own antigens. Although the developing T cell repertoire is constantly purging, self-recognition events do exist when such tight control is evaded and autoreactive lymphocytes escape the thymus (the sites of T cell development) and migrate to the periphery. Upon activation these autoreactive cells may exert aggressive behavior toward one's own tissues and organs leading to autoimmune disease. Multiple sclerosis, Rheumatoid arthritis, and type I diabetes are autoimmune diseases mediated by autoreactive T cells. A logical approach to prevent such autoimmunity would be to reprogram those lymphocytes to tolerate the self antigen. Injection of antigen at the neonatal stage promotes a state of tolerance such that successive encounter with antigen does not precipitate aggressive reactions. The mechanism underlying neonatal tolerance involves priming of T cells whose effector functions do not cause inflammatory reactions upon recognition of antigen but rather induce protective immunity. This form of tolerant immunity provides an attractive strategy for vaccination against autoimmunity. Herein, it is shown that neonatal exposure to a self-peptide-immunoglobulin chimera drives a tolerant immunity toward the self-peptide and protects against the autoimmune disease, experimental allergic encephalomyelitis.

Animals↗

PubMed2000

Newer insights into the pathogenesis of experimental autoimmune thyroiditis.

Experimental autoimmune thyroiditis (EAT), produced in the mouse by immunization with murine thyroglobulin plus complete Freund's adjuvant, represents a valuable model for studying the pathogenesis of human chronic (Hashimoto's) thyroiditis. A major issue requiring clarification is the difference between benign autoimmunity, characterized solely by production of autoantibodies to thyroglobulin, and pathogenic autoimmunity where injury occurs to the thyroid cells. In this article, we describe the role of two key cytokines, IL12 and IFNgamma, in modifying the pathogenic immune response. EAT, defined by cellular infiltration of the thyroid and the development of thyroglobulin-specific autoantibodies, is a dynamic process. Consequently, a cytokine may exert a different effect at different times during the disease process. For purposes of discussion, we propose that there are three stages in the development of EAT: priming; initiation; and progression. Administration of anti-IL12 during the priming stage and initiation dramatically decreases disease and lowers autoantibody levels. In contrast, injection of recombinant IL12 after disease was established significantly decreases the severity of disease and reduces autoantibody levels. Unlike IL-12, IFNgamma was not essential for the priming of EAT. However, the severity of disease in the anti-IFNgamma-treated initiation- and progression-treated animals was higher than in controls, implying a regulatory role for IFNgamma. These findings emphasize that EAT involves a complex array of pathogenic mechanisms. The balance of cytokines produced during the early phase of the autoimmune reaction probably determines the progression from a harmless autoimmune response to autoimmune disease.

Animals↗

PubMedDate not supplied

Experimental studies on genetically determined susceptibility to mercury-induced autoimmune response.

Individual differences in susceptibility may be caused by genetical as well as external variables. In mice as well as rats, autoimmune response can be induced by mercury or gold. The present data demonstrates that the autoimmune response depends qualitatively on the H-2 haplotype. If a strain of mice does not have the susceptible haplotype, no autoimmunity will be induced. However, even among the responding strains significant differences were observed. A clear correlation exists between renal mercury deposition and the autoimmune response in susceptible strains of mice. There was a threshold for induction of the autoimmune response in genetically susceptible mice. When exposure was interrupted, the mercury deposition decreased as did the antinucleolar antibody titre. Thresholds exist within susceptible strains below which no autoimmune response is induced.

Animals↗

PubMed2000

Protective effect of Rolipram in experimental autoimmune neuritis: protection is associated with down-regulation of IFN-gamma and inflammatory chemokines as well as up-regulation of IL-4 in peripheral nervous system.

Rolipram, a phosphodiesterase type 4 inhibitor, is reported to have anti-inflammatory effects. It can markedly downregulate antigen-driven T cell proliferation and suppress TNF-(alpha and TNF-beta production in vitro and in vivo, which have led to its use in the treatment of a number of autoimmune disorders including experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune neuritis (EAN). EAN is a CD4+ T cell-mediated demyelinating autoimmune disease of peripheral nervous system (PNS) that represents an animal model for the study of the immunopathogenesis and immunotherapy of Guillain-Barré syndrome (GBS) in human. In the previous study, we reported that suppression of EAN by Rolipram was associated with down-regulated myelin antigen-induced T cell responses as well as downregulated IFN-gamma and TNF-alpha production. Here we report that EAN induced in Lewis rats by inoculation with the PNS P2 protein peptide 57-81 and Freund's complete adjuvant (FCA), was strongly suppressed by Rolipram administered twice daily intraperitoneally from day 9 post immunization (p.i.), i.e. after onset of clinical EAN to day 18 p.i. This clinical effect was associated with dose-dependent down-regulated production of IFN-gamma and the chemokines macrophage inflammatory protein-1 alpha (MIP-1 alpha, MIP-2 and monocyte chemotactic protein-1(MCP-1) as well as up-regulated IL-4 production in sciatic nerve sections from Rolipram-treated EAN rats at maximum of clinical EAN, i.e. on day 14 p.i.. These findings suggest that Rolipram may be useful in certain T cell-dependent autoimmune diseases and inflammatory neuropathies. These observations call for further studies on the potential role of Rolipram in the treatment of autoimmune diseases.

Animals↗

PubMed2001

Role of cytokines in autoimmune myocarditis and cardiomyopathy.

Cellular as well as humoral autoimmune responses are critically associated with the pathogenesis and progression of myocarditis and cardiomyopathy. Cytokines appear to play critical roles in accentuating or regulating autoimmune mechanisms in these disorders. However, depending on the triggers of autoimmune responses against the heart, such as viral or parasitic infections and experimental immunization with cardiac myosin, the effect of each cytokine on autoimmune myocardial disease may vary. Cytokines may represent new therapeutic targets in the treatment and prevention of autoimmunity-mediated myocarditis and cardiomyopathy, though the etiology and variability in the type of autoimmune responses should be taken into account in the development of cytokine/anti-cytokine treatment of these disorders.

Autoimmune Diseases↗

PubMed1998

Premature ovarian failure: steroid synthesis and autoimmunity.

The androgen biosynthesis and autoimmunity of 25 patients with premature ovarian failure (POF) and 18 control subjects with normal cycles were examined. Serum levels of dehydroepiandrosterone sulfate (DHEAS), 17-hydroxyprogesterone (17-OHP), androstenedione, and testosterone were analyzed in POF patients with or without organ-specific autoimmunity, and the results compared with those of women with normal ovarian function. The comparative analysis of DHEAS, 17-OHP, androstenedione and testosterone showed that POF patients had significantly lower values than normal women (DHEAS, androstenedione and testosterone p < 0.01, 17-OHP p < 0.05). Furthermore, we found one or more organ-specific autoantibodies in 11 patients with POF (44%), while only one woman in the control group showed autoimmunity (antithyroid microsome) (5.5%). Only one patient had both anti-ovarian and anti-adrenal antibodies (4%). The comparison of androgen levels in POF patients with or without autoimmunity revealed a statistically significant reduction of DHEAS levels in POF patients with organ-specific autoimmunity (p < 0.01). These data reveal the reduction in androgen synthesis in POF patients, particularly in those with organ-specific autoimmunity.

17-alpha-Hydroxyprogesterone↗

PubMed1999

Autoimmunity in Waldenström's macroglobulinaemia.

Fifty-seven consecutive patients with Waldenström's Macroglobuliemia were studied retrospectively for autoimmune manifestations. 28 patients or 51% (16 women and 13 men) had clinical and/or serological autoimmune manifestations, two or more of these being concomitant in 20 (12 women and 8 men). The predominant findings were Coombs' positive autoimmune hemolytic anemia (16%), seropositive rheumatoid arthritis (16%), inflammatory gastric ulcer with parietal cell autoantibodies (12%), and IgM-cardiolipin syndrome (11%). 40% of the autoimmune manifestations were present at the time of diagnosis of the Waldenström's Macroglobulinaemia and 60% were observed over a mean period of 4.7 years. All patients had an IgM M-component. There was no correlation between autoimmunity and the size of the M-component or the degree of hypo-IgG and hypo-IgA gammaglobulinemia. The only correlation between autoimmunity and infection was found in patients with gastric ulcer and parietal cell autoantibodies, in whom the infection was caused by Helicobacter pylori.

Aged↗

PubMed2000

Successful TCR-based immunotherapy for autoimmune myocarditis with DNA vaccines after rapid identification of pathogenic TCR.

The identification of TCRs of autoimmune disease-inducing T cells within a short period of time is a key factor for designing TCR-based immunotherapy during the course of the disease. In this study, we show that experimental autoimmune carditis-associated TCRs, Vbeta8.2 and Vbeta10, were determined by complementarity-determining region 3 (CDR3)-spectratyping analysis and subsequent sequencing of the CDR3 region of spectratype-derived TCR clones. Immunotherapy targeting both Vbeta8.2 and Vbeta10 TCRs using mAbs and DNA vaccines significantly reduced the histological severity of experimental autoimmune carditis and completely suppressed the inflammation in some animals. Since depletion or suppression of one of two types of effector cells does not improve the severity of the disease significantly, combined TCR-based immunotherapy should be considered as a primary therapy for T cell-mediated autoimmune diseases. TCR-based immunotherapy after rapid identification of autoimmune disease-associated TCRs by CDR3 spectratyping can be applicable, not only to animal, but also to human autoimmune diseases whose pathomechanism is poorly understood.

Amino Acid Sequence↗

PubMed2002

C1q deficiency and autoimmunity: the effects of genetic background on disease expression.

Gene-targeted C1q-deficient mice have been shown to develop a syndrome reminiscent of human systemic lupus erythematosus with antinuclear Abs and proliferative glomerulonephritis. Initial phenotypic analysis conducted in (129 x C57BL/6) hybrid mice showed that background genes were a significant factor for the full expression of the autoimmune disease. To assess the contribution of background genes in the expression of the autoimmune phenotype, the disrupted C1qa gene was backcrossed for seven generations onto C57BL/6 and MRL/Mp(+/+) strains. These were intercrossed with C57BL/6.lpr/lpr and MRL/Mp-lpr/lpr strains to generate C1q-deficient substrains. In C1q-deficient C57BL/6 mice, no evidence of an autoimmune phenotype was found, and C1q deficiency in both the C57BL/6.lpr/lpr and MRL/Mp-lpr/lpr strains did not modify the autoimmune phenotype observed in wild-type controls. However, in C1q-deficient MRL/Mp(+/+) animals an acceleration of both the onset and the severity of antinuclear Abs and glomerulonephritis was seen. Disease was particularly pronounced in females, which developed severe crescentic glomerulonephritis accompanied by heavy proteinuria. In addition, the C1q-deficient MRL/Mp(+/+) mice had an impairment in the phagocytic clearance of apoptotic cells in vivo. These data demonstrate that the expression of autoimmunity in C1q-deficient mice is strongly influenced by other background genes. The work also highlights the potential value of the C1q-deficient MRL/Mp(+/+) strain as a tool with which to dissect further the underlying mechanisms of the autoimmune syndrome associated with C1q deficiency.

Animals↗