Anti-Pituitary and Anti-Hypothalamus Autoantibody Associations with Inflammation and Persistent Hypogonadotropic Hypogonadism in Men with Traumatic Brain Injury.

Traumatic brain injury (TBI) and can lead to persistent hypogonadotropic hypogonadism (PHH) and poor outcomes. We hypothesized that autoimmune and inflammatory mechanisms contribute to PHH pathogenesis. Men with moderate-to-severe TBI (n = 143) were compared with healthy men (n = 39). The TBI group provided blood samples 1-12 months post-injury (n = 1225). TBI and healthy control (n = 39) samples were assayed for testosterone (T) and luteinizing hormone (LH) to adjudicate PHH status. TBI samples 1-6 months post-injury and control samples were assayed for immunoglobulin M (IgM)/immunoglobulin G (IgG) anti-pituitary autoantibodies (APA) and anti-hypothalamus autoantibodies (AHA). Tissue antigen specificity for APA and AHA was confirmed via immunohistochemistry (IHC). IgM and IgG autoantibodies for glial fibrillary acid protein (GFAP) (AGA) were evaluated to gauge APA and AHA production as a generalized autoimmune response to TBI and to evaluate the specificity of APA and AHA to PHH status. An inflammatory marker panel was used to assess relationships to autoantibody profiles and PHH status. Fifty-one men with TBI (36%) had PHH. An age-related decline in T levels by both TBI and PHH status were observed. Injured men had higher APA IgM, APA IgG, AHA IgM, AHA IgG, AGA IgM, and AGA IgG than controls (p < 0.0001 all comparisons). However, only APA IgM (p = 0.03) and AHA IgM (p = 0.03) levels were lower in the PHH than in the non-PHH group in multivariate analysis. There were no differences in IgG levels by PHH status. Multiple inflammatory markers were positively correlated with IgM autoantibody production. PHH was associated with higher soluble tumor-necrosis-factor receptors I/II, (sTNFRI, sTNFRII), regulated on activation, normal T-cell expressed and secreted (RANTES) and soluble interleukin-2-receptor-alpha (sIL-2Rα) levels. Higher IgM APA, and AHA, but not AGA, in the absence of PHH may suggest a beneficial or reparative role for neuroendocrine tissue-specific IgM autoantibody production against PHH development post-TBI.

Targeting gut microbiota and barrier function with prebiotics to alleviate autoimmune manifestations in NOD mice.

AIMS/HYPOTHESIS: Adopting a diet containing indigestible fibre compounds such as prebiotics to fuel advantageous bacteria has proven beneficial for alleviating inflammation. The effect of the microbial changes on autoimmunity, however, remains unknown. We studied the effects of prebiotic xylooligosaccharides (XOS) on pancreatic islet and salivary gland inflammation in NOD mice and tested whether these were mediated by the gut microbiota. METHODS: Mother and offspring mice were fed an XOS-supplemented diet until diabetes onset or weaning and were compared with a control-fed group. Diabetes incidence was monitored, insulitis and sialadenitis were scored in histological sections from adult mice, and several metabolic and immune variables were analysed in mice before the development of diabetes. Gut barrier function was assessed using an in vivo FITC-dextran permeability test. The importance of XOS-mediated gut microbial changes were evaluated in antibiotic-treated mice fed either XOS or control diet or given a faecal microbiota transplant from test animals. RESULTS: Diabetes onset was delayed in the XOS-fed mice, which also had fewer cellular infiltrations in their pancreatic islets and salivary glands. Interestingly, insulitis was most reduced in the XOS-fed groups when the mice were also treated with an antibiotic cocktail. There was no difference in sialadenitis between the dietary groups treated with antibiotics; the mice were protected by microbiota depletion regardless of diet. Faecal microbiota transplantation was not able to transfer protection. No major differences in glucose-insulin regulation, glucagon-like peptide-1, or short-chain fatty acid production were related to the XOS diet. The XOS diet did, however, reduce gut permeability markers in the small and large intestine. This was accompanied by a more anti-inflammatory environment locally and systemically, dominated by a shift from M1 to M2 macrophages, a higher abundance of activated regulatory T cells, and lower levels of induction of natural killer T cells and cytotoxic T cells. CONCLUSIONS/INTERPRETATION: Prebiotic XOS have microbiota-dependent effects on salivary gland inflammation and microbiota-independent effects on pancreatic islet pathology that are accompanied by an improved gut barrier that seems able to heighten control of intestinal diabetogenic antigens that have the potential to penetrate the mucosa to activate autoreactive immune responses.

Pituitary pathology in traumatic brain injury: a review.

PURPOSE: Traumatic brain injury most commonly affects young adults under the age of 35 and frequently results in reduced quality of life, disability, and death. In long-term survivors, hypopituitarism is a common complication. RESULTS: Pituitary dysfunction occurs in approximately 20-40% of patients diagnosed with moderate and severe traumatic brain injury giving rise to growth hormone deficiency, hypogonadism, hypothyroidism, hypocortisolism, and central diabetes insipidus. Varying degrees of hypopituitarism have been identified in patients during both the acute and chronic phase. Anterior pituitary hormone deficiency has been shown to cause morbidity and increase mortality in TBI patients, already encumbered by other complications. Hypopituitarism after childhood traumatic brain injury may cause treatable morbidity in those survivors. Prospective studies indicate that the incidence rate of hypopituitarism may be ten-fold higher than assumed; factors altering reports include case definition, geographic location, variable hospital coding, and lost notes. While the precise pathophysiology of post traumatic hypopituitarism has not yet been elucidated, it has been hypothesized that, apart from the primary mechanical event, secondary insults such as hypotension, hypoxia, increased intracranial pressure, as well as changes in cerebral flow and metabolism may contribute to hypothalamic-pituitary damage. A number of mechanisms have been proposed to clarify the causes of primary mechanical events giving rise to ischemic adenohypophysial infarction and the ensuing development of hypopituitarism. CONCLUSION: Future research should focus more on experimental and clinical studies to elucidate the exact mechanisms behind post-traumatic pituitary damage. The use of preventive medical measures to limit possible damage in the pituitary gland and hypothalamic pituitary axis in order to maintain or re-establish near normal physiologic functions are crucial to minimize the effects of TBI.

The role of autoimmunity in pituitary dysfunction due to traumatic brain injury.

PURPOSE: Traumatic brain injury (TBI) is one of the most common causes of mortality and long-term disability and it is associated with an increased prevalence of neuroendocrine dysfunctions. Post-traumatic hypopituitarism (PTHP) results in major physical, psychological and social consequences leading to impaired quality of life. PTHP can occur at any time after traumatic event, evolving through various ways and degrees of deficit, requiring appropriate screening for early detection and treatment. Although the PTHP pathophysiology remains to be elucitated, on the basis of proposed hypotheses it seems to be the result of combined pathological processes, with a possible role played by hypothalamic-pituitary autoimmunity (HPA). This review is aimed at focusing on this possible role in the development of PTHP and its potential clinical consequences, on the basis of the data so far appeared in the literature and of some results of personal studies on this issue. METHODS: Scrutinizing the data so far appeared in literature on this topic, we have found only few studies evaluating the autoimmune pattern in affected patients, searching in particular for antipituitary and antihypothalamus autoantibodies (APA and AHA, respectively) by simple indirect immunofluorescence. RESULTS: The presence of APA and/or AHA at high titers was associated with an increased risk of onset/persistence of PTHP. CONCLUSIONS: HPA seems to contribute to TBI-induced pituitary damage and related PTHP. However, further prospective studies in a larger cohort of patients are needed to define etiopathogenic and diagnostic role of APA/AHA in development of post-traumatic hypothalamic/pituitary dysfunctions after a TBI.

Microbe-metabolite-host axis, two-way action in the pathogenesis and treatment of human autoimmunity.

The role of microorganism in human diseases cannot be ignored. These microorganisms have evolved together with humans and worked together with body's mechanism to maintain immune and metabolic function. Emerging evidence shows that gut microbe and their metabolites open up new doors for the study of human response mechanism. The complexity and interdependence of these microbe-metabolite-host interactions are rapidly being elucidated. There are various changes of microbial levels in models or in patients of various autoimmune diseases (AIDs). In addition, the relevant metabolites involved in mechanism mainly include short-chain fatty acids (SCFAs), bile acids (BAs), and polysaccharide A (PSA). Meanwhile, the interaction between microbes and host genes is also a factor that must be considered. It has been demonstrated that human microbes are involved in the development of a variety of AIDs, including organ-specific AIDs and systemic AIDs. At the same time, microbes or related products can be used to remodel body's response to alleviate or cure diseases. This review summarizes the latest research of microbes and their related metabolites in AIDs. More importantly, it highlights novel and potential therapeutics, including fecal microbial transplantation, probiotics, prebiotics, and synbiotics. Nonetheless, exact mechanisms still remain elusive, and future research will focus on finding a specific strain that can act as a biomarker of an autoimmune disease.

Selenium and Autoimmune Diseases: A Review Article.

BACKGROUND: Selenium is an essential trace element with fundamental effects on human biology. Trace elements deficiency is not an uncommon finding in autoimmune diseases. This deficiency may be a consequence of autoimmune diseases or may contribute to their etiology. With regard to evidence showing the association between selenium deficiency and generation of reactive oxygen species and subsequent inflammation, reviewing the role of selenium in collagen vascular diseases could help researchers to devise strategies for managing these diseases. OBJECTIVE: The present study aimed to evaluate the role of selenium and autoimmune rheumatic diseases. DATA SOURCES: PubMed, Scopus, Science Direct, and Google Scholar. STUDY ELIGIBILITY CRITERIA: All the studies on the use of selenium without any limitations in terms of the preparation method, administration route, or formulation process were included in the study. The exclusion criteria were: 1) Articles published in languages other than English, 2) Administration of chemical and hormonal drugs rather than selenium, 3) Investigation of the effects of selenium on the autoimmune problems in animal models, and 4) Insufficiency of the presented data or poor description of the applied methods. Furthermore, review articles, meta-analyses, expert opinions, editorial letters, case reports, consensus statements, and qualitative studies were excluded from the study. DATA EXTRACTION: In this systematic review, articles were evaluated through searching following keywords in combination with selenium: "autoimmune rheumatic diseases "or "scleroderma" or "systemic sclerosis" or "Behcet's disease" or "Sjögren syndrome" or "systemic lupus erythematosus" or "musculoskeletal diseases" or "rheumatoid arthritis" or "vasculitis" or "seronegative arthritis" or "antiphospholipid antibody syndrome". RESULTS: Of 312 articles, 280 were excluded and 32 articles were entered in this study. Based on the majority of studies assessing selenium level in patients with collagen vascular diseases, lower selenium levels were observed in these patients. Moreover, the majority of articles showed an improvement in clinical symptoms of collagen vascular diseases compared to controls after the treatment of patients with different dosages of L-selenomethionine. CONCLUSION: A decrease in the serum level of selenium was noted in patients with autoimmune diseases, which may be a risk factor for inflammation and initiation of autoimmunity in these patients. A sufficient quantity of selenium has been shown to contribute to the management of complications of autoimmune diseases and even improved survival in patients with autoimmune diseases, which may be due to the anti-inflammatory effects of selenium. Since this issue is of clinical importance, it can be considered in potential nutrition interventions and have beneficial effects on some autoimmune diseases.

Aplicaciones terapéuticas de las inmunoglobulinas humanas en Pediatría / Therapeutic applications of human immunoglobulines in Pediatrics

En la actualidad existen diversos productos farmacéuticos constituidos por inmunoglobulinas (fundamentalmente IgG), purificadas por diversos métodos, lo que implica que pueden ser administradas por diversas vías (intramuscular, intravenosa y subcutánea). Estos productos tienen un amplio espectro de indicaciones en diversas enfermedades. Las inmunoglobulinas son los efectores finales de la respuesta inmune humoral, por lo que sus indicaciones fundamentales incluyen la terapia de reemplazo en enfermedades que cursan con déficit en la producción de anticuerpos, las situaciones en que se necesita de manera inmediata la presencia de anticuerpos neutralizantes, como en las terapias posexposición, y en enfermedades que cursan con disrregulación de la respuesta inmune(AU)

There are presently several pharmaceuticals made up of immunoglobulines (fundamentally IgG) purified by several methods, which means that they can be administered by different routes (intramuscularly, intravenously and subcutaneously). These products have a wide spectrum of prescriptions for several diseases. The immunoglobulins are the final effectors of the humoral immune response, so their fundamental prescriptions cover replacement therapies in diseases with antibody production deficit, situations requiring immediate presence of neutralizing antibodies such as post-exposure therapies, and diseases with immune response deregulation(AU)

Aplicaciones terapéuticas de las inmunoglobulinas humanas en Pediatría / Therapeutic applications of human immunoglobulines in Pediatrics

En la actualidad existen diversos productos farmacéuticos constituidos por inmunoglobulinas (fundamentalmente IgG), purificadas por diversos métodos, lo que implica que pueden ser administradas por diversas vías (intramuscular, intravenosa y subcutánea). Estos productos tienen un amplio espectro de indicaciones en diversas enfermedades. Las inmunoglobulinas son los efectores finales de la respuesta inmune humoral, por lo que sus indicaciones fundamentales incluyen la terapia de reemplazo en enfermedades que cursan con déficit en la producción de anticuerpos, las situaciones en que se necesita de manera inmediata la presencia de anticuerpos neutralizantes, como en las terapias posexposición, y en enfermedades que cursan con disrregulación de la respuesta inmune

There are presently several pharmaceuticals made up of immunoglobulines (fundamentally IgG) purified by several methods, which means that they can be administered by different routes (intramuscularly, intravenously and subcutaneously). These products have a wide spectrum of prescriptions for several diseases. The immunoglobulins are the final effectors of the humoral immune response, so their fundamental prescriptions cover replacement therapies in diseases with antibody production deficit, situations requiring immediate presence of neutralizing antibodies such as post-exposure therapies, and diseases with immune response deregulation

Vitamin D deficiency, autoimmunity, and graft-versus-host-disease risk: Implication for preventive therapy.

The majority of patients after allogeneic stem cell transplantation (HSCT) are expected to have vitamin D deficiency early post HSCT due to poor nutritional status and limited sun exposure. The importance of vitamin D in the immune system has been well defined during the past several years, as vitamin D has demonstrated modulatory effects on the immune system through B and T-lymphocyte, macrophage, monocyte, and dendritic cell regulations, which are the effector cells involved in graft-versus-host-disease (GVHD) pathophysiology after HSCT. High-dose early replacement of vitamin D might attenuate autoimmune reactions and decrease severity of GVHD. In this article, we discuss the hypothetical link between early vitamin D deficiency and GVHD and its potential therapeutic role in GVHD and long-term bone loss after HSCT.

Early involvement of nitric oxide in mechanisms of pathogenesis of experimental autoimmune uveitis induced by interphotoreceptor retinoid-binding protein (IRBP).

INTRODUCTION: Autoimmune uveitis is a group of HLA-associated inflammatory diseases of the eye, prevalent worldwide, that may cause blindness. It can be limited to the eye, or associated with a systemic syndrome. Furthermore, patients suffering from uveitis exhibit high serum and local nitric oxide (NO) levels as a consequence of cellular responses to immunologically privileged antigens within the eye such as interphotoreceptor retinoid binding protein (IRBP). To investigate NO production kinetics in autoimmune uveitis and its implication in mechanisms of ocular pathogenesis, we first attempted to develop an experimental model of autoimmune uveitis (EAU) on the Wistar rat, using the whole bovine retinal interphotoreceptor matrix extract (IPMe) and isolated IRBP. MATERIAL AND METHODS: Female Wistar rats (n=24) were divided into three experimental groups: "control rats" (n=3) consisting of non-immunized animals, "IRBP-immunized rats" (n=12) and "IPMe-immunized rats" (n=9), which received a subcutaneous injection, respectively, of 13 µg IRBP and 100 µg IPMe emulsified in complete Freund's adjuvant. On days 7, 14 and 21 post immunization, the rats were sacrificed. Nitrites were assessed in plasma and in homogenate of eyes using the Griess reaction. Meanwhile, eyes were collected for histological studies. RESULTS: Our results show the sensitivity of the Wistar strain to both IPMe and IRBP-induced EAU. In fact, we observed histological disorders affecting the retinal tissue in both models of EAU. On the other hand, a significantly increased production of NO in plasma and homogenate of eyes was also observed in comparison to the control group. Moreover, we noted with interest that maximal production of NO occurs prior to the alteration of retinal tissue. CONCLUSION: In summary, our results suggest the early involvement of NO in the mechanisms of pathogenesis of EAU. NO can be considered as a key bio-marker of poor prognosis in ocular autoimmune inflammation.

Maternal food consumption during pregnancy and risk of advanced ß-cell autoimmunity in the offspring.

BACKGROUND: Evidence for a putative role of maternal diet during pregnancy in the development of ß-cell autoimmunity in the child is scarce. The authors study the association of food consumption during pregnancy and the development of ß-cell autoimmunity in the offspring. SUBJECTS AND METHODS: A prospective Finnish birth cohort of 4297 infants with human leukocyte antigen (HLA)-DQB1-conferred susceptibility to type 1 diabetes and their mothers. Blood samples were collected from the children at 3-12 months intervals to measure type 1 diabetes-associated antibodies: antibodies against islet cells (ICA), insulin, glutamate dehydroxylase, and islet antigen 2. The mothers completed a validated food frequency questionnaire. The end-point was repeated positivity for ICA together with at least one of the other three antibodies. Piecewise-exponential survival models were used. The effective sample size was 3723, with 138 end-points. The median follow-up time was 4.4 years. RESULTS: Maternal consumption of butter, low-fat margarines, berries, and coffee were inversely associated with the development of advanced ß-cell autoimmunity in the offspring, adjusted for genetic risk group and familial diabetes. These associations for low-fat margarines (use vs. non-use HR 0.60, 95% CI: 0.38-0.93, p = 0.02), berries (continuous variable HR 0.90, 95% CI: 0.83-0.98, p = 0.02) and coffee (highest quarter vs. lowest HR 0.62, 95% CI: 0.40-0.97, p = 0.04), remained significant when adjusting for potential confounding sociodemographic, perinatal, and other dietary factors. CONCLUSIONS: In this study assessing total food consumption of the mother during pregnancy, only few among the 27 food groups tested were weakly related to the development of advanced ß-cell autoimmunity in Finnish children.

Fundamentals of clinical immunotoxicology.

Whereas animal studies are invaluable for screening various chemical and drugs for immunotoxic potential, such systems are necessarily limited in their predictive value for humans given the differences in physiology, immune system structure and function, and various other parameters between humans and nonhuman animals. However, prospective experimental studies in humans are not always practical or ethical. What is needed is an approach for combining animal data, human data collected in the course of clinical studies, and modern tools of bioinformatics and systems biology. In this chapter, we will explore current assays and methodologies for assessing immunotoxic potential in humans using this multi--parameter approach.

The risks of free copper in the body and the development of useful anticopper drugs.

PURPOSE OF REVIEW: To review the toxicity and risks of free copper in Wilson's disease, Alzheimer's disease, other disease of neurodegeneration, and cognitive loss in the general population. We will also review the anticopper drugs and how lowering free copper levels with an anticopper drug inhibits fibrosis, inflammation, and autoimmunity. RECENT FINDINGS: Some exciting recent work indicates that free copper levels are increased in Alzheimer's disease, and copper may be involved in disease pathogenesis, opening the way to possible therapy of Alzheimer's disease with anticopper drugs. Copper may also be involved in other diseases of neurodegeneration. A very exciting recent study indicts high intake of copper, mostly from copper supplements, in conjunction with a high-fat diet in more rapid cognitive decline in the general population. Other data indicate that even low levels of copper in drinking water, perhaps similar to copper supplements, bypasses the liver, enters the circulation, increases the blood-brain penetration of copper, and may cause damage. SUMMARY: Some of the implications are that Alzheimer's disease and other diseases of neurodegeneration and fibrotic, inflammatory, and autoimmune diseases may be treatable by lowering the availability of free copper. People in the general population may wish to take steps to lower their free copper levels and, in particular, to abstain from taking copper supplements and ingesting significant amounts of copper in drinking water.

Persistence of residual beta cells and islet autoimmunity during increasing duration of diabetes in NOD mice and experimental approaches toward reversing new-onset disease with bioactive peptides.

The precise fate of beta cells and the presence of islet infiltrates after onset of type 1 diabetes have not yet been fully characterized. Recently we showed that in newly diabetic NOD mice an appreciable number of beta cells remain. This was also observed during the first 2 weeks of diabetes in NOD mice without treatment with insulin. However, the mean number of beta cells per unit islet cross-sectional area decreased with increasing duration of disease. In contrast, glucagon and somatostatin cell numbers showed an increase. The persistence of insulitis in several islets until 4 weeks of diabetes suggests ongoing beta cell autoimmunity over a protracted phase. Combined daily treatment of newly diabetic NOD mice with epidermal growth factor (EGF) and gastrin for the first 14 days of diabetes resulted in temporary restoration of normoglycemia in 7 of 15 mice. We speculate that the residual beta cells present soon after onset of diabetes may respond to experimental regeneration. Treatment of newly diabetic NOD mice with the bioactive peptides EGF and gastrin resulted in partial and temporary reversal of diabetes. We propose that peptide therapies combined with other benign immunomodulatory approaches to rescue and preserve beta cells in the long term and to prevent recurring autoimmunity may be more effective than peptide therapy alone in reversing diabetes in NOD mice.

Immune-based regulation of adult neurogenesis: implications for learning and memory.

Neurogenesis, the formation of new neurons from stem/progenitor cells, occurs in the hippocampal dentate gyrus throughout life. Although the exact function of adult hippocampal neurogenesis is currently unknown, recent studies suggest that the newly formed neuronal population plays an important role in hippocampal-dependent cognitive abilities, including declarative memory. The process of adult neurogenesis is greatly influenced by the interaction between cells of the adaptive immune system and CNS-resident immune cells. Our laboratory has recently demonstrated that immune cells contribute to maintaining life-long hippocampal neurogenesis. The regulation of such immune-cell activity is crucial: too little immune activity (as in immune deficiency syndromes) or too much immune activity (as in severe inflammatory diseases) can lead to impaired hippocampal neurogenesis, which could then result in impaired hippocampal-dependent cognitive abilities. From these converging discoveries arise a mechanism that can explain one route by which our body affects our mind.

Fatty acids, the immune response, and autoimmunity: a question of n-6 essentiality and the balance between n-6 and n-3.

The essentiality of n-6 polyunsaturated fatty acids (PUFA) is described in relation to a thymus/thymocyte accretion of arachidonic acid (20:4n-6, AA) in early development, and the high requirement of lymphoid and other cells of the immune system for AA and linoleic acid (1 8:2n-6, LA) for membrane phospholipids. Low n-6 PUFA intakes enhance whereas high intakes decrease certain immune functions. Evidence from in vitro and in vivo studies for a role of AA metabolites in immune cell development and functions shows that they can limit or regulate cellular immune reactions and can induce deviation toward a T helper (Th)2-like immune response. In contrast to the effects of the oxidative metabolites of AA, the longer-chain n-6 PUFA produced by gamma-linolenic acid (18:3n-6, GLA) feeding decreases the Th2 cytokine and immunoglobulin (Ig)G1 antibody response. The n-6 PUFA, GLA, dihomo-gamma-linolenic acid (20:3n-6, DHLA) and AA, and certain oxidative metabolites of AA can also induce T-regulatory cell activity, e.g., transforming growth factor (TGF)-beta-producing T cells; GLA feeding studies also demonstrate reduced proinflammatory interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha production. Low intakes of long-chain n-3 fatty acids (fish oils) enhance certain immune functions, whereas high intakes are inhibitory on a wide range of functions, e.g., antigen presentation, adhesion molecule expression, Th1 and Th2 responses, proinflammatory cytokine and eicosanoid production, and they induce lymphocyte apoptosis. Vitamin E has a demonstrable critical role in long-chain n-3 PUFA interactions with immune functions, often reversing the effects of fish oil. The effect of dietary fatty acids on animal autoimmune disease models depends on both the autoimmune model and the amount and type of fatty acids fed. Diets low in fat, essential fatty acid deficient (EFAD), or high in long-chain n-3 PUFA from fish oils increase survival and reduce disease severity in spontaneous autoantibody-mediated disease, whereas high-fat LA-rich diets increase disease severity. In experimentally induced T cell-mediated autoimmune disease, EFAD diets or diets supplemented with long-chain n-3 PUFA augment disease, whereas n-6 PUFA prevent or reduce the severity. In contrast, in both T cell- and antibody-mediated autoimmune disease, the desaturated/elongated metabolites of LA are protective. PUFA of both the n-6 and n-3 families are clinically useful in human autoimmune-inflammatory disorders, but the precise mechanisms by which these fatty acids exert their clinical effects are not well understood. Finally, the view that all n-6 PUFA are proinflammatory requires revision, in part, and their essential regulatory and developmental role in the immune system warrants appreciation.

BAFF: B cell survival factor and emerging therapeutic target for autoimmune disorders.

The prevailing treatment strategies for autoimmune disorders employ global immunosuppressants that have harmful side effects with long-term use. A new vision for drug development relies on the generation of therapeutics that have specific and narrow targets, such as pathogenic cell populations. The cellular processes that initiate and maintain B cell dysregulation are not well understood and autoimmune disease results, in part, from the survival and activation of self-reactive B cells. Such B cells produce tissue-damaging pathogenic autoantibodies. BAFF (B cell-activating factor belonging to the TNF family), a member of the TNF family of ligands, may play a role in B cell-mediated diseases. BAFF is a survival factor for peripheral B cells. When BAFF is overexpressed in mice, B cell number and immunoglobulin production is increased and an autoimmune-like phenotype is observed. Mouse models of lupus-nephritis have been shown to exhibit increased serum BAFF levels correlating with disease severity, and many autoimmune patients were found to have higher levels of circulating BAFF than healthy volunteers. Thus, modulating the level and activity of BAFF in these patients may alleviate symptoms associated with their disease. Several potential therapeutic inhibitors targeting BAFF are under investigation, including an anti-BAFF antibody and receptor-Fc fusion proteins.

Unique therapeutic effects of the Japanese-Chinese herbal medicine, Sairei-to, on Th1/Th2 cytokines balance of the autoimmunity of MRL/lpr mice.

Sairei-to, one of the Japanese-Chinese herbal medicines has been used for the treatment of various diseases, especially collagen disease and edema in nephrotic syndrome. However, the mechanism of the therapeutic effects remains uncertain. Therefore, we investigated the immunological changes of skin, kidney, spleen cells and serum in autoimmune-prone MRL/lpr, MRL/n and C57BL/6J mice treated with Sairei-to. In MRL/lpr mice treated with Sairei-to, the improvement of proteinuria, reduction in the number of hematoxylin bodies in kidney, and reduced serum levels of blood urea nitrogen were observed. These results indicate that Sairei-to can improve or inhibit the progression of lupus nephritis. The proportion of CD19 and the serum levels of IgG1, which is one of the pathogenesis of lupus dermatoses and lupus nephritis, were significantly reduced in Sairei-to-treated MRL/lpr mice. Therefore, it is suspected that the B cell function was suppressed by Sairei-to. In addition, CD4/8 ratio in spleen cells and the degree of lymphoproliferation in MRL/lpr mice also decreased. Interestingly, IL-4 producing spleen cells were increased significantly by ELISPOT assay, and IFN-gamma mRNA expressions were reduced in Sairei-to-treated MRL/lpr mice. Regarding the Th balance, an imbalance towards Th1 predominance may play a significant role in MRL/lpr mice, and the Th1 axis was suppressed and the Th2 axis became predominant in Sairei-to-treated MRL/lpr mice. On the other hand, Th2 cell type immunoglobulins (IgG1) were suppressed. These results suggested that Sairei-to is potential for impairing shifted Th1/Th2 balance and hypergammaglobulinemia resulting in therapeutic effects.

n-3 fatty acids and the immune system in autoimmunity.

In short-term studies, both in animals and in humans, fish oil seems to exert anti-inflammatory effects. However, these effects may vanish during long-term treatment. There is a possibility that in autoimmune diseases, supplementation of dietary n-3 fatty acids might lead to a decrease in the number of autoreactive T cells via apoptosis, as demonstrated in (NZBXNZW) F1 lupus mice [40]. Thus, the "fade away" effect might be due to regrowth of pathogenic autoreactive cells. In animal models of autoimmune diseases, diets high in n-3 fatty acids from fish oil increase survival and reduce disease severity in spontaneous autoantibody-mediated disease, while n-6 linoleic acid-rich diets appear to increase disease severity. The situation in human disease is probably more complex. Some of the discrepancy between studies can be attributed to methodologic problems. The effect of fish oil is dose, time and disease-dependent. Since the anti-inflammatory effects depend on the balance between n-3 and n-6 fatty acids, the relative proportion of EPA and DHA and possibly co-treatment with dietary vitamin E, the dose/effect ratio may vary between individuals. Furthermore, some animal studies demonstrating efficacy used very high doses that may be incompatible with human consumption. It seems that fish oil is only mildly effective in acute inflammation. In those chronic inflammatory disorders where it was found to be effective, several weeks are necessary to exhibit results. Yet, this mild anti-inflammatory effect, possibly through downregulation of pro-inflammatory cytokine production, leads to striking therapeutic improvement in critically ill patients. Fish oil supplementation seems advantageous especially in acute and chronic disorders where inappropriate activation of the immune system occurs. Fish oil has only a mild effect on active inflammation of diseases such as rheumatoid arthritis, SLE and Crohn's disease, but it could prevent relapse (in some of the studies). In diseases where the inflammation is mild, such as IgA nephropathy, fish oil may slow or even prevent disease progression. The above could explain the observation in some populations of a decreased incidence of inflammatory and autoimmune diseases [3], since the constant consumption of n-3 fatty acids could suppress any autoreactive (or hyper-reactive) T cells. However, if there is already an existing disease, increased consumption might not be beneficial over a long period. Therefore, the use of n-3 fatty acids can be recommended to the general healthy population, not only to prevent atherosclerosis but possibly also to reduce the risk of autoimmunity.