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PubMed2004

Differential macrophage expression of IL-12 and IL-23 upon innate immune activation defines rat autoimmune susceptibility.

Rodents typically demonstrate strain-specific susceptibilities to induced autoimmune models such as experimental arthritis and encephalomyelitis. A common feature of the local pathology of these diseases is an extensive infiltration of activated macrophages (MPhi). Different functional activation states can be induced in MPhi during innate immune activation, and it is this differential activation that might be important in susceptibility/resistance to induction or perpetuation of autoimmunity. In this study, we present an extensive, comparative analysis of the activation phenotypes of MPhi derived from autoimmune-susceptible and autoimmune-resistant rat strains to describe a cellular phenotype that defines the disease phenotype. We included investigation of receptor function, intracellular signaling pathways, cytokines, and other soluble mediators released after activation of cells using a panel of stimuli embracing many activation routes. We report that activation of MPhi from the autoimmune-susceptible strain was associated with alternative activation indicated by induction of arginase activity, a lower production of classical proinflammatory mediators, and a high production of interleukin (IL)-23, and MPhi from the autoimmune-resistant strains were associated with a higher production of proinflammatory mediators, a classical activation phenotype, and preferential induction of IL-12. These MPhi phenotypes thus reflect disparate, genetic cellular programs that define autoimmune susceptibility.

Animals↗

PubMed2002

Impaired processing of brief, rapidly presented auditory cues in infants with a family history of autoimmune disorder.

Studies have shown that individuals with language disorders, such as developmental dyslexia and specific language impairment, exhibit impairments in the processing of brief, successive, or rapidly changing auditory information. It is also the case that a higher rate of autoimmune disorders have been identified in those with language-based learning disorders and, conversely, that individuals with autoimmune disorders show a higher incidence of language-related disorders. The rapid auditory processing (RAP) deficits described for older individuals with language impairments may also be used as a behavioral marker to identify infants at higher risk for language delays. Thus, we were interested in examining RAP abilities in a subset of infants with a positive family history of autoimmune disorders. Eleven infants from our ongoing prospective longitudinal studies were identified based on parental response to a question about the presence of a family history of autoimmune disease and compared to 11 matched controls. The RAP threshold of each infant was assessed at 6 and 9 months of age using a conditioned head-turn procedure (using tone pairs with brief interstimulus intervals) and an auditory-visual habituation-recognition memory task using computer-generated consonant-vowel syllables (/ba/ vs. /da/). A visual habituation-recognition memory task that did not require processing of brief temporal cues was also administered. Group differences emerged on the infant RAP tasks, and on language outcome measures at 12 and 16 months of age. Infants from families with a history of autoimmune disorder had significantly higher (i.e., poorer) RAP thresholds and lower language scores than did control infants, whereas visual discrimination scores did not differ between family history infants and controls. Moreover, when brief auditory cues were necessary for the discrimination of /ba/ vs. /da/, infants with a family history of autoimmune disorder performed significantly more poorly than did controls. These findings lend support to the hypothesis that a similar mechanism, perhaps a neural-immune interaction, may underlie the observed co-occurrence of autoimmune disorders and learning impairments.

Acoustic Stimulation↗

PubMed1994

Autoimmune thyroid disease: further developments in our understanding.

The revolution in molecular techniques has allowed dissection of the autoimmune response in a way impossible to imagine 10 yr ago. There have been spectacular advances in our understanding of self-tolerance mechanisms and how these may fail, combined with a detailed comprehension of antigen presentation, functional T cell subsets, and TCR utilization in autoimmunity, albeit usually in animal models that resemble, but do not exactly duplicate, human diseases. More gradually, these findings are being translated to thyroid autoimmunity, where the major achievement of the last decade has been the molecular characterization of the three main thyroid autoantigens. This in turn has allowed epitope identification, although again the only clear data so far have come from animal models of EAT. Another advance has been the recognition that the thyrocyte is not a helpless target of autoaggression, being capable of expressing a wide array of immunologically active molecules, which may exacerbate or diminish the autoimmune response. In 1983, there was considerable excitement at the discovery of the first of these phenomena, namely MHC class II expression, but its possible role in autoantigen presentation remains to be defined. By analogy with pancreatic beta-cells, and based on our own data, we believe that class II-expressing thyrocytes have little, if any, such role and suspect that instead this may be a mechanism for inducing peripheral tolerance. Defining the contribution of thyrocytes to the intrathyroidal autoimmune response, whether from released cytokines or surface-bound molecules, will be crucial to our future understanding, as well as holding the promise that these thyroid-derived products might be therapeutic targets. Despite molecular developments in HLA analysis, there have been no really major improvements in our understanding of the immunogenetics of thyroid autoimmunity, equivalent to those made in type 1 diabetes mellitus. The available data suggest strongly that non-MHC genes play an important role in susceptibility, and novel approaches will be required to identify these. On the other hand, we know more about the importance of environmental and endogenous (most probably hormonal) factors in thyroid autoimmunity. Understanding the basic immunological changes in the postpartum period is still poor, however, as most studies to date have concentrated on epidemiology and clinical delineation. As PPTD undergoes spontaneous remission, elucidation of these mechanisms has clear implications for treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1993

Iodine deficiency induces thyroid autoimmune reactivity in Wistar rats.

The last 2 decades it has become clear that iodine deficiency has a modulating effect on the thyroid autoimmune response in humans. Also, in animals that spontaneously develop autoimmune thyroid disease, evidence is accumulating that a low iodine intake can modulate thyroid autoimmune reactivity. However, it is still not clear what the effect of a low iodine intake on thyroid autoimmune reactivity is in normal nonautoimmune animals. To study the relationship of a dietary low iodine intake on the thyroid autoimmune reactivity in nonautoimmune animals, normal Wistar rats (female) were kept on an enriched iodine diet (daily iodine intake of 100 micrograms iodine), a "for our area normal" (conventional) diet (COD; daily iodine intake of 7 micrograms iodine), a low iodine diet (LID; 2 days of 1% KCLO4, followed by iodine-deficient drinking water/pellets), or an extremely low iodine diet (LID+; 1% KCLO4 continuously in the drinking water and iodine-deficient pellets). The enriched iodine diet rats were euthyroid (T3, approximately 8 nM/liter: T4, approximately 50 nM/liter; TSH, approximately 2 ng/ml), had a normal thyroid weight (approximately 12.5 mg), and showed only minimal signs of local thyroid immune reactivity; low numbers of intrathyroidal dendritic cells (DC; approximately 35 DC/mm2), CD4+ cells (approximately 2 cells/mm2), and CD8+ cells (approximately 2.5 cells/mm2) were found in combination with low anticolloid antibody production (incidence of positive animals, 12.5%). The COD resulted in a normal thyroid function. The rats were euthyroid (range of T3, 1.6-1.2 nM/liter; T4, approximately 50 nM/liter; TSH, approximately 2 ng/ml) and had a normal thyroid weight (approximately 12.5 mg). However, some signs of thyroid autoimmune reactivity were found [number of intrathyroidal DC, approximately 40/mm2; approximately 3 CD4-positive (CD+) cells/mm2; approximately 3 CD8+ cells/mm2; together with a 30% incidence of anticolloid antibodies]. The LID and LID+ not only induced goiter formation [thyroid weight, 27.3 +/- 4.2 mg (mean +/- SD) after 12 weeks of LID and 38.4 +/- 5.3 mg after 4 weeks of LID+] and low production of T4 by the thyroid [28 +/- 3 nM/liter (mean +/- SD)] after 12 weeks of LID and 14 +/- 3 nM/liter after 2 weeks of LID+], but also induced various signs of thyroid autoimmune reactivity.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2002

Longitudinal study of vasopressin-cell antibodies and of hypothalamic-pituitary region on magnetic resonance imaging in patients with autoimmune and idiopathic complete central diabetes insipidus.

Diagnosis of autoimmune central diabetes insipidus (CDI) is based on the presence of autoantibodies to AVP-secreting cells (AVPcAb) or the coexistence of other autoimmune polyendocrine syndromes; moreover, it can be also suggested by the presence of lymphocytic infundibulo-neurohypophysitis, evidenced by biopsy of pituitary stalk and/or by pituitary stalk thickening on magnetic resonance imaging (MRI). However, so far, in clinical CDI patients with lymphocytic infundibulo-neurohypophysitis, AVPcAb have not been investigated and in those with or without autoimmune polyendocrine syndromes (APS), longitudinal studies on the behavior of AVPcAb alone, or of both AVPcAb and hypothalamic pituitary imaging on MRI are lacking. Aim of this work was to investigate in these patients the occurrence of AVPcAb (by indirect immunofluorescence) and of pituitary stalk thickening (by MRI) and their longitudinal changes during a follow-up period. We studied 22 patients, aged 29-53, with APS and complete CDI, grouped as follows: 10 with recent onset (< or =1.5 yr) of CDI (group 1a) and 12 with CDI of long-term duration (> or = 7 yr) (group 1b); moreover, a group of 13 patients with apparent idiopathic CDI of recent onset (<1.5 yr) were studied. They were divided, on the basis of the detection of AVPcAb as follows: 5 AVPcAb positive patients (aged 19-26) classified as isolated autoimmune CDI (group 2) and 8 AVPcAb negative patients (aged 21-26), classified as true idiopathic CDI (group 3). All patients were evaluated yearly, along 5 yr, for AVPcAb and for hypothalamic-pituitary region imaging. At study entry, 8/10 (80%) of patients in group 1a and 7/12 (58.3%) in group 1b were positive for AVPcAb and persisted positive subsequently, during all the follow-up period, even if at lower titers. All patients in group 2 were positive and all those in group 3 were negative for AVPcAb and persisted positive and negative, respectively, for all the follow-up study. Among the AVPcAb-positive patients, only 5 in group 1a and 2 in group 2 showed also pituitary stalk thickening at the first observations, which however spontaneously disappeared subsequently indicating a possible lymphocytic infundibulo-neurohypophysitis. All patients in the studied groups showed loss of the hyperintense signal of the neurohypophysis on MRI at entry and during all the follow-up period. Results of this longitudinal study suggest: 1) AVPcAb, frequently present at high titers in recent phases of CDI, persist subsequently, even if at lower titers, several years after the onset of disease. 2) The occurrence of a lymphocytic infundibulo-neurohypophysitis suggested by the pituitary stalk thickening on MRI only in patients positive for AVPcAb confirms a further autoimmune variant of CDI also in these cases. 3) The longitudinal behavior of patients in group 3 suggests that the absence of AVPcAb at the onset of clinical idiopathic CDI is able to exclude a subsequent appearance of these antibodies and consequently an autoimmune involvement in CDI of these patients. Instead the finding of AVPcAb in several patients with only CDI, thought at first clinical observation as idiopathic, indicates that the prevalence of autoimmune CDI must be considered much higher than that so far reported.

Adult↗

PubMed1999

Outer causes inner conflicts: environment and autoimmunity.

Autoimmune diseases are some of the most common yet least understood maladies in medicine today. Some estimates place the number of sufferers of such diseases as high as 20% of the U.S. population, most of them women. The disorders involved range from the familiar to the relatively uncommon to the obscure. What these disorders have in common is that they cause the immune system to attack the body's own tissues. Uncertainty in the field of autoimmune disease extends even to the fundamental questions of what an autoimmune disease is and how many people are affected; identifying specific environmental risk factors for autoimmune diseases is still highly speculative. To gain some sense of direction, scientists are looking at a few documented environmental exposures that have led to autoimmune syndromes, as well as some animal models that exhibit autoimmune syndromes similar to those seen in humans. At a September 1998 NIEHS workshop on environmental links to autoimmune diseases, participants prioritized research needs in five main categories, a step that should help scientists develop strategies for investigating this family of diseases.

Animals↗

PubMed1999

Gender and risk of autoimmune diseases: possible role of estrogenic compounds.

A striking common feature of many autoimmune diseases in humans and experimental animals, despite differences in pathology, is that females are highly susceptible to autoimmune conditions compared to males. In several animal models, estrogens promote, whereas androgens abrogate, B-cell-mediated autoimmune diseases. To understand mechanisms by which estrogens regulate autoimmunity, it is first necessary to decipher estrogen effects on the normal immune system. Estrogen treatment of nonautoimmune mice diminished lymphocyte numbers in both developmental and mature lymphoid organs. Estrogen dysregulated T- and B-cell balance by inducing selective T-cell hypoactivity and B-cell hyperactivity. Even though estrogen did not alter the relative percentages of splenic T-cell subsets, splenic lymphocytes had a reduced proliferative response to T-cell stimulants and were refractory to rescue from activation-induced apoptosis compared to cells from placebo-treated mice. In contrast, estrogen induced B-cell hyperactivity (promoted autoantibodies to double-stranded DNA and phospholipids, increased numbers of plasma cells, and increased autoantibody yield per B cell). Note that treatment of normal mice with estrogen can alter T- and B-cell regulation and overcome B-cell tolerance to result in autoimmunity in normal individuals. Could environmental estrogens promote some human autoimmune disorders? Is there a link between environmental estrogens and autoimmune disorders, especially since these disorders are reported possibly more frequently? These provocative questions warrant investigation. Our findings on immunomodulatory effects may serve as a benchmark to examine whether endocrine-disrupting chemicals will have similar immunologic effects.

Animals↗

PubMed2004

The emerging role of the CTLA-4 gene in autoimmune endocrinopathies.

It is thought that the majority of autoimmune endocrinopathies, including Graves' disease, autoimmune hypothyroidism, type 1 diabetes mellitus and autoimmune Addison's disease (sporadic and as well as autoimmune polyendocrinopathy syndrome type 2) are inherited as complex genetic traits. Multiple genetic and environmental factors interact with each other to confer susceptibility to these disorders. In recent years there have been considerable efforts towards defining susceptibility genes for complex traits. These investigations have shown, with increasing evidence, that the cytotoxic T lymphocyte antigen-4 (CTLA-4) gene is an important susceptibility locus for autoimmune endocrinopathies and other autoimmune disorders. Here we review the genetic and functional analyses of the CTLA-4 locus in autoimmune endocrinopathies, and discuss the recent efforts in fine-mapping this locus.

Addison Disease↗

PubMed2002

T-cell vaccination for autoimmune diseases: immunologic lessons and clinical experience in multiple sclerosis.

Autoreactive T-cells are regulated under the normal conditions and play an important role in autoimmune pathologies when they are dysregulated as a result of genetic, environmental and other unknown factors associated with various autoimmune diseases. The immune regulation of autoreactive T-cells may be regained by activating the regulatory network, such as the idiotype anti-idiotypic network. Immunization with inactivated autoreactive T-cells (T-cell vaccination) can be used as a powerful means of activating the idiotype anti-idiotypic network to deplete specific subsets of autoreactive T-cells potentially involved in autoimmune conditions. It induces regulatory immune responses that closely resemble the in vivo situation, where the immune system is challenged by clonal activation and expansion of given T-cell populations in various autoimmune diseases. Recent clinical trials in multiple sclerosis have begun to reveal the role of T-cell vaccination in the understanding of in vivo regulation of autoreactive T-cells and in the development of effective therapeutic strategies for multiple sclerosis and other autoimmune conditions. In this article, we will review the recent advances in T-cell vaccination in relationship to the regulatory mechanism induced by T-cell vaccination and the potential of T-cell vaccination as a treatment for T-cell-mediated autoimmune diseases. Current issues and thoughts related to the preparation of T-cell vaccine, the relevant sources of autoimmune T-cells and epitope spreading are also discussed.

Animals↗

PubMed2006

Clinical and biochemical features of autoimmune hepatitis in 36 pediatric patients.

BACKGROUND: Few studies on autoimmune hepatitis have enrolled non-Caucasian groups. AIMS: To evaluate Brazilian children with type 1 and 2 autoimmune hepatitis regarding outcome and clinical and biochemical parameters. PATIENTS AND METHODS: Thirty-six patients were submitted to a protocol that evaluated the clinical history, physical and biochemical data, and the course of the disease. Twenty-four children had type 1 autoimmune hepatitis, seven had type 2 and five had unclassified autoimmune hepatitis. Most patients were females (77%), with a median age at diagnosis of 11 years, and the median duration of symptoms was 5.5 and 8 months for types 1 and 2, respectively. Jaundice and choluria were the most common clinical manifestations. RESULTS: Treatment with azathioprine and prednisone was successful in patients with type 1 and 2 autoimmune hepatitis. AST and ALT decreased after 4 to 8 weeks of treatment compared to pretreatment levels in type 1 autoimmune hepatitis. Increased GGT values returned to pretreatment levels after 1 year in the two types. Three patients died and three other patients underwent liver transplantation. CONCLUSIONS: Non-Caucasian children had a similar disease when compared to Caucasian ones with autoimmune hepatitis. Increased levels of GGT during the first year of treatment should not be the only parameter for the indication of cholangiopathy.

Adolescent↗

PubMed1994

Genetic predisposition of autoimmune disease and B-cell chronic lymphocytic leukemia (B-CLL).

Autoimmune disease is a polygenic disease in which various genetic factors play crucial roles. The familial clustering and the association of HLA haplotypes have been well-recognized. There is a close association between chronic lymphocytic leukemia (CLL) and autoimmune disease. Like autoimmune diseases, CLL is the type of leukemia most often occurring among close relatives. The patients with CLL frequently share common HLA haplotypes with relatives with autoimmune disease. As the majority of CLL is of CD5+ B-cell type, and as CD5+ B cells are suggested to be involved in autoimmunity, certain regulatory abnormalities in the proliferation and differentiation of CD5 B cells may be involved in both B-CLL and autoimmune disease. I discuss here the possibility that different, but related, MHC haplotypes would predispose either to autoimmune disease or to B-CLL, based on our findings obtained from MHC (H-2)-congenic New Zealand mouse strains.

Animals↗

PubMed2006

Gene therapy strategies towards immune tolerance to treat the autoimmune diseases.

Autoimmune diseases such as type 1 diabetes and multiple sclerosis pose a significant health burden on our society. As a whole, autoimmune diseases affect approximately 6% of the population and are the third largest disease burden after heart disease and cancer. Such pathologic manifestations arise by way of damaging reactions of B-cell derived antibodies and/or T-cells to self-antigens and are triggered by genetic and environmental factors. Currently there is no known cure, with treatment restricted to toxic, long-term immunosuppressive regimes, replacement therapy and in intractable cases, transplantation of autologous or allogeneic haematopoietic stem cells. In experimental models of autoimmunity, gene therapeutic approaches have demonstrated promise in treating the autoimmune diseases. These include delivery of anti-inflammatory cytokines and exploitation of regulatory T cells. However, none of these approaches provide lasting, long-term benefit. We hypothesise that therapeutically transduced haematopoietic stem cells followed by transplantation is an alternative strategy to establish permanent immune tolerance that can not only prevent autoimmunity but also cure these diseases. Our approach is focused on directing autoimmune disease-specific autoantigen expression in the thymus by genetic manipulation of haematopoietic stem cells to establish molecular chimeras. Our hypothesis originates from experimental studies with a mouse model of experimental autoimmune gastritis (EAG) and more recently with the non-obese diabetic (NOD) mouse model for type 1 diabetes (T1D).

Animals↗

PubMed2002

The immunosuppressive activity of proinflammatory cytokines in experimental models: potential for therapeutic intervention in autoimmunity.

The role of cytokines in the pathogenesis of T cell-mediated diseases, and in particular autoimmune responses, has been the subject of intense investigation in the past few years. Transgenic strains of mice have been generated, each expressing individual cytokines in organs targeted by autoimmunity. These animal models provide the most advanced tool available for analyzing the relationship between cytokines and T-dependent autoimmune responses. On the one hand, these experiments confirm that the local expression of proinflammatory cytokines is pivotal in initiating and maintaining pathogenic responses to self. On the other hand, and somewhat unexpectedly, these models have also revealed that cytokine factors controlling autoimmunity can act both as potentiating and inhibitory agents, depending upon the site and timing of exposure. As a result, one major concept emerging from different experimental models, including those originally established in our laboratory, is that proinflammatory cytokines may ameliorate autoimmunity. In this review, we analyze the mechanisms whereby cytokines that are considered as proinflammatory may in contrast suppress immune responses to self antigens. Besides emphasizing that the proinflammatory/immunogenic properties of a given cytokine may not be an intrinsic property, we review evidence that the regulation imposed by the cytokine network on autoimmunity is a finely tuned balance between activation and downmodulation of an individual autoreactive T cell repertoire. By emphasizing that factors such as the duration of cytokine exposure and the type of cell population involved strongly influence that balance, we underline the potential therapeutic implications of cytokine-mediated modulation of autoimmunity.

Animals↗

PubMed1994

Antibodies to islet 37k antigen, but not to glutamate decarboxylase, discriminate rapid progression to IDDM in endocrine autoimmunity.

Apart from islet cell antibodies (ICAs), antibodies to glutamate decarboxylase (GAD), insulin autoantibodies (IAAs), and a novel islet antigen (37k antigen) are potential markers for insulin-dependent diabetes mellitus (IDDM). GAD is also an antigen in stiff-man syndrome (SMS), and both SMS and IDDM are associated with ICAs and autoimmunity to other endocrine organs. We investigated possible links between antibody responses to islet antigens with autoimmunity to other endocrine organs and determined which specific antibodies can identify individuals who progress to IDDM. Antibodies to GAD were detected in > or = 90% of both diabetic and nondiabetic patients with ICAs and other endocrine autoimmunity, in 59% of ICA-positive IDDM patients without endocrine autoimmunity, in all patients with SMS, but in only 1-3% of healthy (nondiabetic) and autoimmune disease control subjects. GAD antibody levels were increased in ICA-positive IDDM patients with polyendocrine autoimmunity compared with those without. In contrast, antibodies to 37k antigen were only detected in patients who developed acute-onset IDDM. IAAs were also associated with IDDM. Thus, certain factors enhance antibody responses to GAD in polyendocrine autoimmunity, but this does not necessarily lead to development of IDDM or SMS. Antibodies to 37k antigen are strongly associated with acute-onset IDDM and are useful serological markers for disease.

Adolescent↗

PubMed2003

The significance of autoimmunity in the pathogenesis of Chagas heart disease.

Chagas heart disease develops in approximately one-third of individuals infected with the protozoan parasite Trypanosoma cruzi. Among the many possible mechanisms responsible for this illness, an autoimmune mechanism has received much experimental support during the past several decades. Initial observations of the absence or near absence of parasites from the inflamed tissues suggested the autoimmunity hypothesis, and the finding of measurable autoimmune responses in humans and experimental animals has bolstered this idea. The rigorous testing of the hypothesis has been difficult, primarily because other mechanisms are likely to play a role during active infection, particularly immunity to parasite antigens that may persist in the infected animal. While the role autoimmunity plays in disease pathogenesis is not known, it is clear that autoimmune responses are induced during infection of some humans and animals. A number of mechanisms may explain the induction of autoimmunity during T. cruzi infection, including parasite-induced polyclonal lymphocyte activation, molecular mimicry, bystander activation, and presentation of cryptic self epitopes. The genetic makeup of both the parasite and host are also critical to the outcome of infection. The autoimmune hypothesis deserves further exploration, while public health interventions should focus on control of the insects that transmit the parasite, development of parasiticidal drugs and vaccines, and testing of blood products, which have become an important threat of new infections.

Animals↗

PubMed1994

B-1 cells in systemic autoimmune responses: IgM+, Fc epsilon Rdull B cells are lost during chronic graft-versus-host disease but not in murine AIDS or collagen-induced arthritis.

The potential role of B-1 cells (i.e. the CD5+ B cell and "sister" B cell subsets) in autoimmunity is controversial. CD5+ B cells have been shown to secrete antibodies of similar specificity as those found in many systemic autoimmune diseases; in addition, increases in CD5+ B cell frequency have been reported in patients suffering from rheumatoid arthritis, Sjögren's syndrome, myasthenia gravis, insulin-dependent diabetes mellitus and Hashimoto's thyroiditis. Whether these increases are due to expansion of B-1 lineage cells in the human or due to activation-induced expression of CD5 by conventional B cells is unclear. In the present study, we used three murine models of systemic autoimmunity: murine acquired immunodeficiency syndrome (MAIDS), chronic graft-versus-host disease (cGvHD), and collagen-induced arthritis (CIA) to determine whether increases in B-1 cell frequency are universally seen in models of autoimmunity which are mechanistically distinct. In contrast to the aforementioned human systemic autoimmune diseases which exhibit an increase in CD5+ B cell frequency, the percentage of CD5+ B cells declined in all three murine models of systemic autoimmune disease. Even though there was a decrease in the frequency of CD5+ B cells there was no change in the actual number of CD5+ B cells. Thus, the apparent decline in CD5+ B cell frequency was due to increases in either T cells, conventional Fc epsilon R+ B cells, or both. The only actual decline in a B cell subset was the loss of IgM+, Fc epsilon Rdull cells in both the spleen and peritoneal cavity of mice undergoing a chronic graft-versus-host reaction. Therefore, our data suggests that expansion of the B-1 subset does not occur as a general feature of murine systemic autoimmune disease. These observations, consistent with previous studies of Ig gene usage in autoreactive antibodies, support the view that expansion and differentiation of the CD5+ B cell subset is not a central event leading to autoantibody production.

Animals↗

PubMed1996

Differential involvement of Th1 and Th2 cytokines in autoimmune diseases.

By virtue of their functional antagonism, Th1 cells or cells producing the same cytokines as Th1 cells may behave as "suppressor cells' with respect to Th2 cells and vice versa. An excessive Th1- or Th2-like response may favor the development of different autoimmune diseases. As can be expected from their physiological role, Th-1 cytokines participate in autoimmune diseases with a preferential delayed type hypersensitivity component, i.e. in those diseases in which cytotoxic T cells attack organ-specific target cells. Autoimmune diseases with a predominant Th1 component include experimental autoimmune encephalitis and insulin-dependent diabetes mellitus. In contrast, Th2-type responses participate in systemic autoimmune diseases with a strong humoral component. Such diseases probably include certain drug-induced states of autoaggression, namely mercury-induced autoimmune disease and chlorpromazine-induced autoimmunity. It is tempting to speculate that therapeutic interventions designed to recover a normal Th1/Th2 balance will provide a useful etiological strategy for the re-establishment of self-tolerance.

Animals↗

PubMed1992

Effects of calorie restriction on immunologic functions and development of autoimmune disease in NZB mice.

Chronic energy (calorie) intake restriction (CEIR) prolonged life, inhibited autoimmune disease, and influenced immunologic and hematologic parameters in NZB mice. Abnormalities in numbers and proportions of T and B cells populations were corrected. Deficient responses to phytomitogens, mixed lymphocyte reactions, formation of plaque-forming cells to sheep red blood cells in vitro, production of cytotoxic T lymphocytes after in vitro stimulation, and interleukin 2 production were also corrected. CEIR prevented the extreme splenomegaly that normally occurs with age in NZB mice. This influence was associated with reduction of a greatly expanded non-T, non-B lymphoid cell population. Calorie restriction also prevented in NZB mice the rapid decrease in total numbers of colony-forming B cells in bone marrow that is also characteristic of mice of this strain. The influences of CEIR on immune parameters and hematopoiesis were generally less marked in non-autoimmune-prone DBA/2 mice than in autoimmune-prone NZB mice. CEIR has been shown to produce profound influences on several strains of autoimmune-prone mice (NZB x NZW)F1, MRL/lpr, BXSB, and NZB herein). In each of these strains, the pathogenesis and manifestations of autoimmune disease are dissimilar. Therefore, it seems likely that calorie restriction acts on an as yet elusive mechanism that operates to foster development of the diseases associated with aging common to each of these autoimmune strains as well as autoimmune-resistant mice and rats. Further investigation of the molecular and cellular bases of the benefits of CEIR seems urgent.

Animals↗