Connections between the immune system and the nervous system.

From the initial observations by Zinkernagel and Doherty over 40 years ago of the need for T cells to recognize "altered self," our understanding of TCR recognition of peptide+ MHC has made significant advances. However, alongside a more detailed understanding of the interaction comes additional questions around precisely why T cells must limit themselves to MHC, when a greater range of ligand binding is demonstrably possible, and mechanistically, how MHC restriction achieves the necessary T cell survival and activation signals. The answer may well lie in the study of noncanonical or poorly signaling TCRs to understand the absolute requirements for effective TCR-pMHC recognition, continued advances in structural biology providing resolution of multimolecular complexes, and cryo-EM providing information on the dynamics of molecular localization and organization before and after TCR ligation of pMHC.

A major barrier to axonal regeneration in mammals is the unfavorable extracellular environment that develops following injury to the central nervous system (CNS). In particular, three myelin-associated inhibitory proteins (MAIs) – Nogo, myelin-associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMgp) – are known to inhibit axonal regeneration and functional recovery. These MAIs share a common receptor, glycosylphosphatidylinositol-anchored Nogo receptor (NgR). However, paired immunoglobulin-like receptor B (PirB) – which was originally identified as a receptor for class I major histocompatibility complex (MHCI) in the immune system – is also expressed in neurones and plays a similarly inhibitory role in axonal regeneration and synaptic plasticity following CNS injury through its association with MAIs. Importantly, suppression of PirB activity through antibody antagonism or genetic means can partially relieve the inhibition of neurite outgrowth in vitro and in vivo. In this review, we present the molecular features, expression patterns and known signaling pathways of PirB, and we specifically focus on putative roles for PirB in the CNS and its potential as a target of molecular therapies for enhancing axonal regeneration and synaptic plasticity following CNS injury.

Research into the effects of host genetics on HIV disease susceptibility and progression, and on the efficacy and toxicity of drug treatment, occupies a particular position in the landscape of HIV research...

Peptides presented by the major histocompatibility complex (MHC) are derived from the degradation of cellular proteins. Thus, the repertoire of these peptides (the MHC peptidome) should correlate better with the cellular protein degradation scheme (the degradome) than with the cellular proteome. To test the validity of this statement and to determine whether the majority of MHC peptides are derived from short lived proteins, from defective ribosome products, or from regular long lived cellular proteins we analyzed in parallel the turnover kinetics of both MHC peptides and cellular proteins in the same cancer cells. The analysis was performed by pulse-chase experiments based on stable isotope labeling in tissue culture followed by capillary chromatography and tandem mass spectrometry. Indeed only a limited correlation was observed between the proteome and the MHC peptidome observed in the same cells. Moreover a detailed analysis of the turnover kinetics of the MHC peptides helped to assign their origin to normal, to short lived or long lived proteins, or to the defective ribosome products. Furthermore the analysis of the MHC peptides turnover kinetics helped to direct attention to abnormalities in the degradation schemes of their source proteins. These observations can be extended to search for cancer-related abnormalities in protein degradation, including those that lead to loss of tumor suppressors and cell cycle regulatory proteins.

An antigen will be able to stimulate an immune response if the antigen has been presented and recognized by T-cells. Major Histocompatibility Complex (MHC) molecules are molecules that will recognize and present the peptides of the antigen. In humans, two classes of MHC are known to carry out this role, namely Class-I MHC and Class-II MHC, while Class-III MHC has a function that is not directly related to peptide binding. The genes that code for MHC molecules are so polymorphic that each individual is certain to have a different allele (heterozygous). In Class-I MHC, only the α-chain is polymorphic while in Class-II MHC both α and β-chains are polymorphic. MHC polymorphism will affect (1) the ability to create immune responses including antibody production, (2) resistance or susceptibility to infectious diseases, and (3) resistance or susceptibility to autoimmune and allergic diseases. That is why MHC is so polymorphic. The immune system has to fight many different pathogens. By having many different MHC molecules, one can present widely different antigens and can spur an effective immune response.

Oligodendrocytes Enforce Immune Tolerance of the Uninfected Brain by Purging the Peripheral Repertoire of Autoreactive CD8+ T Cells

More than a decade has passed since the publication of the first report implicating T cells in the bone loss induced by ovariectomy (ovx).1 Since then there has been extraordinary progress in the understanding of the regulatory network that links the hemopoietic and the mesenchymal compartments of the bone marrow (BM), the interactions between the immune system and bone, and the role of lymphocytes as mediators of the effects of calciotrophic hormones in bone. Collectively this body of knowledge has led to the firm establishment of "osteoimmunology" as a novel discipline and a promising area of investigation. The objective of this perspective is to revisit the exciting hypothesis that T cells play a pivotal role in the mechanism of ovx-induced bone loss. The bone-sparing activity of estrogens is due to a repression of bone remodeling coupled with a balancing effect on bone formation and resorption.2 The dominant acute effect of estrogen is the blockade of new osteoclast formation, cells which arise by cytokine-driven proliferation and differentiation of monocyte precursors that circulate within the hematopoietic cell.3 This process is facilitated by BM stromal cells (SCs), which provide physical support for nascent osteoclasts and produce soluble and membrane-associated factors essential for the proliferation and differentiation of osteoclast precursors. This inhibitory effect on osteoclastogenesis is associated with a repressive effect on osteoblastogenesis.4 Another critical effect of estrogen is that of increasing osteoclast apoptosis5-7 while blocking the apoptosis of osteoblasts and osteocytes.2, 8 It has been proposed that the effects of estrogens on the generation of osteoblasts and the lifespan of osteoblasts and osteoclasts result from extranuclear actions of the endoplasmic reticulum (ER) and activation of cytoplasmic kinases.2, 7 The decline of ovarian function at menopause results in decreased production of estrogen and a parallel increase in pituitary follicle-stimulating hormone (FSH) levels. The combined effects of estrogen deprivation and elevated FSH production cause a marked stimulation of bone resorption9 and a period of rapid bone loss that is central to the pathogenesis of postmenopausal osteoporosis. In mice the acute effects of menopause are modeled by ovx, a procedure that stimulates bone resorption by increasing osteoclast formation3 and lifespan.5-7 This initial phase of bone loss is followed by a slower but more prolonged loss of mainly cortical bone due to incomplete refilling of the resorption cavities due to insufficient osteoblast (OB) activity and lifespan.10 An expansion of the osteoclastic pool is therefore the key mechanism responsible for the bone loss that occurs early after ovx. The net bone loss caused by ovx is limited, in part, by an increase in bone formation resulting from stimulated osteoblastogenesis.11 This compensation is fueled by an expansion of the pool of BM–SCs, increased commitment of such pluripotent precursors toward the osteoblastic lineage,11 and enhanced proliferation of early OB precursors.4 Subsequent escalations in OB apoptosis12, 13 extensions of osteoclast lifespan5, 6 and increased secretion of cytokines that suppress bone formation, such as interleukin 7 (IL-7) and tumor necrosis factor (TNF), are the likely reasons for why bone formation does not increase as much as resorption after ovx. The stimulatory effect of ovx on SCs is equally relevant for osteoclastogenesis as one of the consequences of estrogen deprivation is the formation of osteoblastic cells with an increased osteoclastogenic activity14; ie, the capacity to support osteoclast formation. Evidence now suggests that T cells play a pivotal role in the mechanism of ovx-induced bone loss. Core observations include reports showing that ovx fails to induce trabecular and cortical bone loss in: T-cell–deficient nude mice,1, 15-17, wild-type (WT) mice deleted of T cells by injection of anti–T cell antibodies,18 mice treated with Abatacept19 (an agent that blocks T cell costimulation and induces T cell anergy and apoptosis)20, 21 and mice lacking the T cell costimulatory molecule CD40 ligand (CD40L).18 The fact that nude mice are protected against ovx-induced bone loss has been confirmed independently.22 By contrast, Lee and colleagues23 showed that nude mice are protected against the loss of cortical, but not trabecular bone induced by ovx. In another study, T-cell–deficient and B-cell–deficient mice were found to lose bone after ovx.24 The discrepancy between our reports1, 15-19, 25 and those of others23, 24 is likely explained by differences in the experimental design, the lack of B cells in some models, and compensatory mechanisms such as an increase in natural killer (NK) cells producing the osteoclastogenic factor IL-17.26 Both CD4+ and CD8+ cells have been found to play a role in ovx-induced bone loss. CD4+ cells include the TH1, Th2, and Th17 subsets. Th17 are regarded as the most osteoclastogenic subset of T CD4+ cells because they produce high levels of IL-17, receptor activator of NF-κB ligand (RANKL), and TNF, and low levels of interferon gamma (IFNγ).27, 28 The differentiation of Th17 is inhibited by estrogen via a direct effect mediated by estrogen receptor alpha (ERα).29 The role of Th17 in ovx-induced bone loss remains to be determined because one study reported that IL-17R–null mice are more susceptible to ovx-induced bone loss than controls,30 while another group found these mice to be protected from ovx-induced bone loss.26 More abundant information is available about regulatory T cells (Tregs), a population capable of suppressing the effector function of TH1, Th2, and Th17 T cells. Tregs are defined by the expression of the transcription factor FoxP3. Tregs inhibit monocyte differentiation into osteoclasts in vitro and in vivo, and blunt bone resorption31, 32 through the secretion of IL-4, IL-10, and transforming growth factor beta 1 (TGFβ1).33 Attesting to the relevance of Tregs, studies have shown that estrogen increases the relative number of Tregs.27, 34 Moreover, transgenic mice overexpressing Tregs develop progressive high bone mass due to inhibition of bone resorption, and are protected against ovx-induced bone loss.35 Moreover, adoptive transfer of Tregs into T cell–deficient mice increases bone mass, indicating that Tregs directly affect bone homeostasis without the need to engage other T cell lineages.35 Two mechanisms have been described to explain how T cells contribute to ovx-induced bone loss (Fig. 1). The first involves an increase in T cell activation, leading to enhanced production of TNF by BM T cells. The second is a regulatory crosstalk between T cells and SCs, resulting in enhanced production of osteoclastogenic cytokines by SCs. Schematic representation of the role of T cells in the mechanism by which ovx promotes osteoclastogenesis, osteoblastogenesis, and hemopoiesis. Estrogen deficiency promotes T cell activation by increasing the interaction of antigen (Ag)-loaded MHC molecules with bone marrow macrophages (BMM) and dendritic cells (DC) with the T cell receptor (TCR). The Ags are likely to be non-self peptides derived from the intestinal macrobiota. T cell activation also requires at least two costimulatory signals provided by the binding of BMM and DC-expressed CD40 and CD80 to the T cell surface molecules CD40L and CD28, respectively. A critical upstream event is the increased production of reactive oxygen species (ROS) that activate DCs by increasing their expression of CD80. The expansion of T cells in the BM is partially driven by an ovx-induced increase in the thymic output of naïve T cells. Activated T cells secrete TNF that stimulates osteoclast formation primarily by potentiating the response to RANKL. In addition, T cell–expressed CD40L and DLK1/FA-1 increase the osteoclastogenic activity of SC by blunting their secretion of OPG and augmenting their production of RANKL, M-CSF, and other proinflammatory factors. The survival of naïve T cells and some memory T cells requires the low-affinity engagement of the T cell receptor (TCR) by a diverse repertoire of self-antigens (Ags) bound to major histocompatibility complex (MHC) molecules expressed on Ag-presenting cells.36, 37 By contrast, binding of foreign Ags such as bacterial Ags with MHC molecules is followed by high-affinity interactions with TCRs that drive T cell activation. Both low-affinity interactions with self-Ags and high-affinity foreign Ag/MHC/TCR interactions are referred to as "Ag presentation." Ovx induces T cell expression of activation markers and promotes T cell proliferation, expansion, and acquisition of effector functions. These are all features of T cells exposed to foreign Ags.36 The gastrointestinal tract is colonized for life with 100 trillion indigenous bacteria, creating a diverse ecosystem known as the microbiota, whose contributions to human health are profound.38 The macrobiota is likely to represent the source of foreign Ag that drives the expansion of T cells induced by ovx. Although direct verification of a role for macrobiota in T cell expansion is still lacking, compelling supportive data are available. For example, adoptive transfer of T cells into T cell–deficient mice is followed by rapid engraftment and expansion of donor T cells into the host. This process is driven by foreign Ags.36 Attesting to a role of the macrobiota, the expansion of transferred T cells into T cell–deficient mice is greatly reduced in host mice raised in a germ-free environment.36 Moreover, mice maintained in germ-free conditions display increased bone mass due to the lack of immune cell activation.39 T cells are key inducers of bone-wasting because ovx increases T cell TNF production to a level sufficient to augment RANKL-induced osteoclastogenesis.1 This effect is due to an increased number of TNF-producing T cells15 and enhanced production of TNF per cell.18, 40 Ovx also increases the population of premature senescent CD4 + CD28–T cells,40 a lineage that produces high levels of TNF. The presence of increased levels of T cell–produced TNF in the BM of ovx animals is well documented.15, 19, 40, 41 Studies have also shown that menopause increases T cell activation and T cell production of TNF and RANKL in humans.42, 43 The role of TNF in ovx-induced bone loss has been demonstrated in multiple models. For example, ovx fails to induce bone loss in TNF-null mice and in animals lacking the p55 TNF receptor.15 Likewise, transgenic mice insensitive to TNF due to the overexpression of a soluble TNF receptor,44 and mice treated with the TNF inhibitor TNF binding protein45 are protected from ovx-induced bone loss. The specific relevance of T cell TNF production in vivo was demonstrated by the finding that although reconstitution of nude recipient mice with T cells from WT mice restores the capacity of ovx to induce bone loss, reconstitution with T cells from TNF-deficient mice does not.15 The mechanism by which estrogen deficiency expands the pool of TNF-producing T cells is summarized in Figure 1 and involves reactivation of thymic function and induction of T cell activation in the BM. T cell activation is driven by enhanced Ag presentation by macrophages and dendritic cells (DCs).46, 47 The thymus undergoes progressive structural and functional decline with age, coinciding with increased circulating sex-steroid levels at puberty.48 By middle age most parenchymal tissue is replaced by fat, and in both mice and humans fewer T cells are produced and exported to secondary lymphoid organs. However, the thymus continues to generate new T cells even into old age.49, 50 In fact, active lymphocytic thymic tissue has been documented in adults up to 107 years of age.51 Under severe T cell depletion secondary to human immunodeficiency virus (HIV) infection, chemotherapy, or bone marrow transplant, an increase in thymic output (known as thymic rebound) becomes critical for long-term restoration of T cell homeostasis. For example, middle-aged women treated with autologous bone marrow transplants develop thymic hypertrophy and a resurgence of thymic T cell output, which contributes to the restoration of a wide T cell repertoire,52 although the intensity of thymic rebound declines with age. The mechanism driving thymic rebound is not completely understood, but one factor involved is IL-7.53 Both androgens and estrogen suppress thymic function.54, 55 Accordingly, castration reverses thymic atrophy and increases export of recent thymic emigrants to the periphery,56 whereas sex steroids inhibit thymic regeneration by promoting thymocyte apoptosis and arresting thymocyte/prelymphocyte differentiation.57 Restoration of thymic function after castration occurs in young58 as well as in very old rodents.59, 60 In accordance with the notion that estrogen deficiency induces a rebound in thymic function, ovx increases the thymic export of naïve T cells.61 Indeed, stimulated thymic T cell output accounts for ∼50% of the increase in the number of T cells in the periphery. Moreover, thymectomy decreases the bone loss induced by ovx by ∼50%, thus demonstrating that the thymus plays a previously unrecognized role in the pathogenesis of ovx-induced bone loss in mice.61 The remaining bone loss is a consequence of the peripheral expansion of naïve and memory T cells. This finding suggests the tantalizing hypothesis that estrogen deficiency–induced thymic rebound may be responsible for the exaggerated bone loss in young women undergoing surgical menopause62 or for the rapid bone loss characteristic of women in their first 5 to 7 years after natural menopause.63 Indeed, an age-related decrease in estrogen deficiency–induced thymic rebound could mitigate the stimulatory effects of sex steroid deprivation and explain why the rate of bone loss in postmenopausal women diminishes as aging progresses.63 The most upstream effects of ovx in the BM are to stimulate the production of reactive oxygen species (ROS) and to impair the generation of antioxidants.10, 19, 64, 65 In response to ovx, ROS are produced by most BM cells, including T cells.41 ROS play an important role in postmenopausal bone loss by generating a more oxidized bone microenvironment.66, 67 Multiple enzymatic pathways regulate the intracellular redox state through modulation of ROS levels.68 Ovx blunts the BM levels of glutathione (GSH), a critical ROS scavenger, and reduces expression of APE1/Ref-1 and Prx-1 proteins, which collectively limit the production of intracellular ROS.69 ROS have important direct effects on osteoblasts and osteoclasts; these effects have been addressed elsewhere.7, 70, 71 However, additional pivotal effects of ROS include expanding the pool of mature DCs that express the costimulatory molecule CD80, and increasing DC-mediated Ag presentation.19 Antioxidants potently inhibit DC differentiation and their ability to activate T cells,72, 73 in part by suppressing expression of MHC class II and costimulatory molecules in response to Ag.74 N-acetyl-cysteine (NAC), which acts as an intracellular scavenger of ROS by restoring intracellular concentrations of GSM, can block DC maturation75 and DC-mediated T cell activation.76 In vivo support for a role of ROS is provided by experiments demonstrating that administration of antioxidants prevents ovx-induced bone loss,19, 64, 70 while depletion of glutathione by buthionine sulfoximine (BSO), which inhibits glutathione synthesis, enhances bone loss.64 Bone loss caused by BSO has significant similarities to bone loss induced by estrogen deficiency, as both processes are TNF-dependent.77 A second, direct upstream effect of estrogen deficiency is to blunt BM levels of TGFβ,78 a powerful repressor of T cell activation. TGFβ acts as an immunosuppressant by inhibiting T cell activation and T cell production of inflammatory cytokines, including IFNγ. Demonstrating the relevance of the repressive effects of TGFβ on T cell function, mice with T cell–specific blockade of TGFβ signaling were found to be completely resistant to the bone-sparing effects of estrogen.16 Gain of function experiments confirmed that elevation of the systemic levels of TGFβ prevents ovx-induced bone loss and bone turnover.16 The key downstream mechanism by which ovx increases Ag presentation by macrophages is a stimulatory effect on the expression of the gene encoding Class II Transactivator (CIITA). The product of CIITA is a non-DNA binding factor induced by IFNγ that functions as a transcriptional coactivator at the MHC II promoter.79 Increased CIITA expression in macrophages results from ovx-mediated increases in IFNγ production by CD4+ T cells and the responsiveness of CIITA to IFNγ.46 This cytokine was initially described as an anti-osteoclastogenic cytokine because it is a potent inhibitor of osteoclastogenesis in vitro.80 The notion that IFNγ is an inhibitor of bone resorption was reinforced by the finding that silencing of IFNγR−/− signaling leads to a more rapid onset of collagen-induced arthritis and bone resorption81 as compared to WT controls, and by the report that IFNγ decreases serum calcium and osteoclastic bone resorption in nude mice.82, 83 Several mechanisms have been proposed to explain the anti-osteoclastogenic activity of IFNγ, including inhibition of RANKL signaling through the degradation of TNF receptor–associated factor 6 (TRAF6),80 stimulation of apoptosis mediated by Fas/FasL signals,84 and inhibition of RANK and c-Fms gene expression.85 However, the finding that IFNγ is an effective treatment for osteopetrosis both in humans86 and rodents87 demonstrates that the net effect of IFNγ in vivo is to stimulate osteoclastic bone resorption. In keeping with a net pro-resorptive effect of IFNγ in vivo are reports demonstrating that IFNγ−/− and IFNγR−/− mice are protected against ovx-induced bone loss.17, 46 Mice lacking IFNγ production are also protected against infection-induced alveolar bone loss,88 whereas in erosive tuberculoid leprosy and psoriatic arthritis IFNγ production correlates positively with tissue destruction.89 In addition, randomized controlled trials have shown that IFNγ does not prevent bone loss in patients with rheumatoid arthritis (RA),90 nor the bone-wasting effect of cyclosporine A.91 Finally, disruption of IFNγ signaling in vivo results in a strong and sustained inhibition of markers of osteoclastic activity.92 These opposing in vitro and in vivo effects of IFNγ are explained by the fact that IFNγ influences osteoclast formation via both direct and indirect effects.17 IFNγ directly blocks osteoclast formation through targeting of maturing osteoclast.93 However, IFNγ is also a potent inducer of antigen presentation and thus of T cell activation. Therefore, when IFNγ levels are increased in vivo, activated T cells secrete pro-osteoclastogenic factors and this activity offsets the anti-osteoclastogenic effects of IFNγ.17 It should also be mentioned that it is now recognized that IFNγ affects bone turnover by promoting the commitment of BM–SCs into the osteoblastic lineage and their differentiation into mature osteoblasts.94 Accordingly, treatment with IFNγ reverses ovx-induced bone loss by promoting bone formation.92 Another mechanism by which estrogen regulates T cell TNF production is by repressing the production of IL-7, a potent lymphopoietic cytokine and an inducer of bone destruction in vivo.95 Attesting to the relevance of this factor, IL-7 levels are significantly elevated following ovx,61, 96 and in vivo IL-7 blockade is effective in preventing ovx-induced bone destruction.96 The elevated BM levels of IL-7 contribute to the expansion of the T cell population in peripheral lymphoid organs through several mechanisms. First, IL-7 directly stimulates T cell proliferation.61 Second, IL-7 increases antigen presentation by upregulating the production of IFNγ. Third, IL-7 and TGFβ regulate The in TGFβ signaling characteristic of estrogen deficiency may to stimulate IL-7 thus driving the of osteoclastogenic cytokine production and bone In estrogen deficiency, IL-7 bone loss by suppressing bone formation and thus bone formation from resorption. A that the crosstalk between T cells and SCs is relevant for ovx-induced bone loss was provided by the finding that activated T cells induce SC apoptosis via the ligand a which blunts the compensatory increase in bone formation that bone loss in ovx More abundant information is available about the T crosstalk driven by the also known as is a key surface ligand expressed on T CD40L to and several CD40 is expressed on cells, hemopoietic and cells of the osteoblastic CD40L has been to because T cells, through the production of the anti-osteoclastogenic factor by B mice a reduced bone due to exaggerated bone bone has also been found in by a in which CD40L production is due to a in the CD40L However, mice lacking T cell–expressed CD40L are protected against hormone bone the that CD40L may in while promoting bone resorption conditions of bone Studies with mice and with WT mice treated with the CD40L have that silencing of CD40L completely prevents ovx-induced bone A mechanism was shown to be First, silencing of CD40L blocks the activation of T cells and the resulting production of TNF. Second, CD40L is for ovx to increase the proliferation and the differentiation of SCs and their capacity to support osteoclast formation through enhanced production of factor and RANKL, and secretion of a critical additional mechanism by which T cells bone homeostasis in ovx mice is through a crosstalk between T cells and SCs that results in enhanced osteoclastogenesis to a enhanced In ovx increases the number of activated T cells that the expression of and RANKL by SCs, and ovx the SC production of The net result is a significant increase in the rate of The interaction of CD40L with CD40 on SCs in the of estrogen deficiency to the effects of costimulation on B cell OPG the of osteoclast formation in of bone loss. An additional mechanism of T crosstalk the novel of bone mass antigen has been for a known as This factor can be to generate a soluble known as In conditions DLK1/FA-1 are produced by SCs, B cells, and T cells. These factors stimulate osteoclastogenesis and block by the production of TNF, IL-7, and other inflammatory cytokines by SCs. Ovx increases the production of DLK1/FA-1 by activated CD4+ and CD8+ T cells, resulting in a stimulation of the production of osteoclastogenic cytokines by SCs. Attesting to the relevance of mice are significantly protected against ovx-induced bone The hypothesis that the immune system is pivotal for the bone loss about by menopause remains to be demonstrated in it remains to the of why the immune system in and is involved in the mechanism of ovx-induced bone loss. may by postmenopausal bone loss as an of an event critical for the need to stimulate bone resorption in the This process is essential to the increased for calcium about by The for this event is the acute in estrogen levels A second to the period is in associated with is by proliferation of the and formation of These are by and is now that regulates and to by the production of RANKL and a system that is for bone homeostasis is also a key of The in levels in the period results in reduced tissue levels of RANK and RANKL, with the effect of the for The increase in the and TNF levels in the BM induced by estrogen levels the of calcium from the to the and then to the a state of to the is induced by an increase in the number of A to the of is the loss of such immune and the restoration of a immune This is through a decrease in the resulting from the acute in steroid levels. However, a between immune to the and bone is provided by the that OPG is expressed by human it is to that of ovarian function induces bone loss through an immune response because natural has these key within the immune system to (Fig. Schematic representation of in the period and of the involved cells and The that estrogen and are followed by a stimulation of bone resorption, to and of immune to the Activated T cells drive bone resorption by TNF. A decrease in the number of Tregs induces the of the immune The loss of OPG may contribute to the and the increased bone resorption. A decrease in levels of RANKL and RANK induce the of the for with increased of calcium from the the in the contribute to an event critical for The data the hypothesis that of ovarian function induces bone loss through an immune response because natural has key within the immune system to The data support the hypothesis that the bone loss induced by estrogen deficiency is due to a complex of hormones and cytokines that to the process of bone Ovx T cell TNF production by increasing T cell activity in the and the peripheral lymphoid organs. T cell precursors the BM and to the T cell and expansion in the of from the these new T cells to peripheral lymphoid including the BM Ovx induces T cell activation in the BM in part by directly promoting antigen and in part via stimulation of IL-7 and IFNγ production and of TGFβ The net result of these actions is an increase in the number of TNF-producing T cells. The elevated levels of TNF increase RANKL-induced osteoclast formation. Estrogen deficiency also T cell activation and osteoclastogenesis by leading to an in The combined effect of IFNγ and ROS enhances Ag T cell activation. T cells stimulate RANKL and production by SCs, through CD40L and The that has of

Herpesviruses have evolved numerous strategies to evade detection by the immune system. Notably, most of the herpesviruses interfere with viral antigen presentation to cytotoxic T lymphocytes (CTLs) by removing class I major histocompatibility complex (MHC) molecules from the infected cell surface. Clearly, since the herpesviruses have evolved an extensive array of mechanisms to remove class I MHC molecules from the cell surface, this strategy serves them well. However, class I MHC molecules often serve as inhibitory ligands for NK cells, so viral downregulation of all class I MHC molecules should leave the infected cell open to NK cell attack. Some viruses solve this problem by selectively downregulating certain class I MHC products, leaving other class I products at the cell surface to serve as inhibitory NK cell ligands. Here, we show that human herpesvirus 7 (HHV-7) U21 binds to and downregulates all of the human class I MHC gene products, as well as the murine class I molecule H-2K(b). HHV-7-infected cells must therefore possess other means of escaping NK cell detection.

Major histocompatibility complex (MHC) molecules are peptide receptors. Their function is to collect peptides inside the cell and transport them to the cell surface, where the complex of peptide and MHC molecule may be recognized by T lymphocytes (Rammensee et al. 1993). In normal cells MHC-associated peptides are derived from normal, self proteins. During their differentiation, T cells become tolerant — by elimination or inactivation (anergy) — to complexes of self MHC and self peptides (Von Boehmer 1992). Thus when new peptides derived from infectious agents or changed self proteins occur later, these can be recognized by T cells (Zinkernagel and Dohenty 1974). However, overexpressed, aberrantly expressed, and even normal self proteins can induce T cell responses under conditions which revert anergy (Nanda and Sercarz 1995). Since the specific immune response is regulated by T cells, the trimolecular complex of T cell receptor (TCR), MHC molecule, and peptides serves as a control switch for the immune system. Control of tumor growth and tumor dissemination by the immune system, particularly by the cellular immune system, is the basis for development of antitumor vaccines (Foley 1953; Prehn and Main 1957; Klein et al. 1960; Old et al. 1962). The role MHC molecules and their associated peptides play in tumor contol is important for development of targeted antigen-specific vaccines for cancer therapy.KeywordsMajor Histocompatibility ComplexHuman Leukocyte AntigenMajor Histocompatibility Complex ClassHuman Leukocyte Antigen ClassMajor Histocompatibility Complex MoleculeThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Major Histocompatibility Complex (MHC) molecules play a crucial role in inducing an adaptive immune response. T-cell epitopes require compatible MHC molecules to form MHC-peptide Complexes (pMHC) that activate the T-cell Receptors (TCR) of T-lymphocyte clones. MHCs are polymorphic molecules with wide varieties of gene alleles. There are two classes of MHC molecules, class I and II. Both classes have three classical loci HLA-A, -B, and –C are present in class I and HLA-DP, -DQ, and -DR in class II. To induce a compatible T-lymphocyte clone, the T-cell epitope requires the association of the compatible MHC molecule to form pMHC. Each MHC variant possesses a different groove that is capable of binding a different range of antigenic epitopes. Without the compatible MHC molecule, a T cell clone cannot be activated by a particular viral epitope. With the aim of preventing viral transmission, the efficiency of a viral vaccine is related to the existence of specific MHC alleles in the individual. This article proposes the roles of the MHC molecule to prevent viral infection. In addition, the association of the viral receptor molecule with the viral infection will also be discussed.

Complex bidirectional signaling occurs between the nervous and immune systems that impacts the functions of both systems. In response to stressors, the central nervous system has modulatory effects on the immune system through release of hormones, paracrine signals, and by direct contacts between nerves and immune cells. Conversely, in response to antigens and pathogens, immune system activation results in production of cytokines that induce altered neural activity. Progressive age‐related decline in brain and immune functions in the elderly results in impaired cognition, reestablishment of homeostasis at age‐ adjusted set points, and immune senescence. This chapter reviews our understanding of how normal aging alters the cross talk between the autonomic nervous system and the immune system to alter immune functions with age. Changes in the relationship between noradrenergic (NA) nerves and immune cells with age have been demonstrated, including altered density and compartmentation of NA nerves in lymphoid organs, norepinephrine (NE) turnover, density and coupling of adrenergic receptors, and availability and functional capacity of target lymphoid cells. Strain‐dependent changes in how NA nerves age in secondary lymphoid tissue have been reported. These changes alter nerve‐to‐immune signaling, and subsequently immune functions in old rodents. These findings suggest that impaired sympathetic regulation of immune function occurs in aged individuals, which may contribute to the increase in susceptibility to infectious diseases, autoimmunity, and cancer in the elderly. Age‐related changes in sympathetic nervous system (SNS) modulation of immune functions are likely to contribute to the reduced immunocompetence observed in clinical studies with elderly subjects. Understanding the age‐related changes that occur in SNS modulation of immune functions could be useful for developing novel strategies for treating diseases, disease prevention, and improving overall health in the elderly. List of Abbreviations: aMNE, a‐methylnorepinephrine; Con A, concanavalin A; CGRP, calcitonin gene‐related peptide; CRH, corticotropin‐releasing hormone; DN, dual negative; DP, dual positive; GM‐ CFU, granulocyte/macrophage colony‐forming units; IFN‐g, interferon‐g; MAO‐B, monoamine oxidase B; MHC, major histocompatibility complex; NA, noradrenergic; NE, norepinephrine; NGF, nerve growth factor; NPY, neuropeptide Y; PALS, periarteriolar lymphatic sheath; SCID, severe combined immunodeficiency; 6‐OHDA, 6‐hydroxydopamine; SNS, sympathetic nervous system; SP, single positive; TH, tyrosine hydroxylase; VIP, vasoactive intestinal polypeptide; SOD, superoxide dismutase

Myelin basic protein (MBP) and proteolipid protein (PLP), the most abundant proteins of central nervous system (CNS) myelin, have been extensively studied as possible primary target antigens in multiple sclerosis (MS), a primary demyelinating autoimmune disease of the CNS. However, there is increasing evidence to suggest that autoimmune reactivity against the quantitatively minor myelin component, myelin oligodendrocyte glycoprotein (MOG), can also play a role in the pathogenicity of MS. We recently demonstrated a predominant response to MOG by peripheral blood lymphocytes from patients with MS tested for their reactivity against various myelin antigens, including MBP and PLP. To ascertain whether or not T cell reactivity to MOG in MS is a potentially pathogenic response, we have tested the ability of synthetic MOG peptides (pMOG) representing potential T cell epitopes, to induce neurological disease in mice. Both strains of mice tested (SJL/J and PL/J mice) were able to mount a primary T cell response to some of the five MOG peptides synthesized, pMOG 1-21, 35-55, 67-87, 104-117 and 202-218. T cell lines could be raised in both strains to pMOG 35-55 and 67-87, but epitope definition revealed that each strain recognized a different minimal epitope within these two peptides. T cell lines to pMOG 1-21 and 202-218 could also be raised in SJL/J and PL/J mice, respectively. T cell reactivity to pMOG 104-117 was not observed in either mouse strain. None of the peptides tested induced detectable clinical signs in SJL/J mice. In contrast, an MS-like chronic relapsing-remitting disease could be induced in PL/J mice with pMOG 35-55. The disease presented with a delayed onset and with clinical signs which differed significantly in their progression and expression from the typical ascending paralysis of experimental autoimmune encephalomyelitis induced with other myelin components, such as MBP and PLP. Histological examination of CNS tissue from mice injected with pMOG 35-55 revealed only mild neuropathological signs with few inflammatory foci in brain and spinal cord. Some myelin splitting and edema were detected upon electron microscopic examination in the spinal cord and cerebellum. Transfer of pMOG 35-55 reactive T cells into naive PL/J mice resulted in pathological changes characterized by inflammatory foci in the brain and spinal cord. This passively induced disease was clinically silent, as was also reported for Lewis rats injected with T cells specific for the same MOG peptide.(ABSTRACT TRUNCATED AT 400 WORDS)

Objective To investigate the clinical and radiological features of children with first attack of inflammatory central nervous system disorders and seropositivity to myelin-oligodendrocyte glycoprotein (MOG). Methods The clinical course, cerebrospinal fluid (CSF), MRI studies, MOG status and outcomes were retrospectively analyzed in children with first attack of inflammatory central nervous system disorders and seropositivity to MOG who were hospitalized in Children′s Hospital of Fudan University from January 2016 to April 2017. Results Thirteen patients including 8 males and 5 females were included in this study, the ratio of male/female was 1.6∶1, and the median age was six years. Ten patients were diagnosed with acute disseminating encephalomyelitis, and three with clinically isolated syndromes. Seven patients had elevated CSF lymphocyte cells, and five patients had elevated CSF protein. All the patients′ sera were tested for the anti-MOG IgG, which ranged from 1∶10 to 1∶100 with cell-based assay. MRI results showed that multiple anatomical areas were involved. Twelve patients had brain lesions, in which 10 patients had multiple lobes involved and four had tumefactive demyelinating lesions. The affected anatomical areas included white matters in 11 cases, thalamus/basal ganglias in nine, corpus callosums in three, brainstems in 10, spinal cord in five. The MRI features were characterized by hazy, bilateral lesions without clear boundaries. Clinical symptoms were fully restored in all the patients after treated with intravenous globulin and methyl prednisone. The average follow-up time was 8.9 months, and none of the patients had clinical recurrence. Conclusions MOG was associated with many kinds of inflammatory demyelinating diseases of central nervous system in children. Most of them were diagnosed with acute disseminating encephalomyelitis which has an acute or sub acute clinical course. The clinical manifestations of patients showed diversity. Multiple anatomical areas were involved, and treatment with intravenous globulin and methyl prednisone was effective in the acute phase. All of the patients had a favorable outcome. Key words: Demyelinating autoimmune diseases, CNS; Glycoproteins; Autoantibodies; Child

Genes of the major histocompatibility complex (MHC) offer several assets that make them unique candidates for studies of adaptation in natural populations (Potts & Wakeland, 1990; Hedrick, 1994). The primary role of the MHC is to recognize foreign proteins, present them to specialist immune cells and initiate an immune response (Klein & Figueroa, 1986). The MHC gene family includes highly polymorphic genes encoding a set of transmembrane glycoproteins that are critical to the generation of immune responses (Kennedy et al., 2002). In general, foreign proteins enter cells either by infection or by phagocytosis into antigenpresenting cells such as macrophages. These foreign proteins are broken down into small peptides and loaded onto specific MHC molecules. The MHC molecule comprises an immunoglobulin stalk, which anchors the molecule to the cell surface, and a basket receptor called antigen-recognizing sites (ARS) located in peptide binding region (PBR). A subset of these protein/MHC complexes are then transported to the cell surface and presented for interrogation by the circulating T-cell population. A complex cascade of immune responses is triggered when the T cell binds to the presented peptide. Two major groups of MHC genes can be distinguished. MHC class I genes play an essential role in the immune defense against intracellular pathogens by binding peptides mainly derived from viral proteins and cancer-infected cells. They are expressed on the surface of all nucleated somatic cells. In contrast, MHC class II genes are predominantly involved in monitoring the extracellular environment by presenting peptides mainly derived from parasites (e.g. bacteria, nematodes, cestodes) to the T-cells. They are primarily expressed on antigen-presenting cells of the immune system, such as B cells and macrophages. Although ARS do show a degree of specificity, a single MHC molecule can bind multiple peptides that have common amino acids at particular anchor positions (Altuvia & Margalit, 2004). Genes within the MHC involved in antigen presentation constitute the most polymorphic loci known in vertebrates (Hedrick, 1994). The polymorphism of the MHC-molecules is associated with the diversity of the T-lymphocyte receptors that in turn determine the disease and parasite resistance of an organism and thus may affect the long-term survival rate of populations (Hedrick et al., 1999; Paterson et al., 1998). The ARS show high levels of polymorphism not only in the number of alleles but also in the sequence variation among alleles (Hughes & Yeager, 1998). The general view is that balancing selection is the determinant role in shaping patterns of nucleotide diversity in MHC genes (Bernatchez & Landry, 2003; Hughes & Nei, 1989).

Neuroinflammation subsumes inflammatory processes in the central nervous system(CNS). The insults causing for neuroinflammation are diverse: infections, traumatic brain injury, toxins, and autoimmunity are among these. In the periphery activated macrophages and dendritic cells represent the first line of defense - the innate immunity. In the central nervous system pro-inflammatory cytokines are released by microglia, the brain resident macrophages, and astrocytes. This induces neuroinflammation. For the progression of various neurodegenerative diseases, including, e.g., Alzheimer's Disease, neuroinflammation, and prolonged immune activity have been identified as a risk factor. In this thesis, I investigated which effects the chronic infection with the parasite Toxoplasma gondii (T. gondii) and thereby prolonged neuroinflammation take on the brains of different laboratory mouse strains. Additionally, I investigated whether these effects are in part mediated by the p75 neurotrophin receptor. Neurotrophins are secreted proteins that belong to a class of growth factors. They have shown to be capable of regulating neuronal survival, differentiation, growth, and maintenance among other. Intriguingly neurotrophins are also expressed and secreted by microglia and other cell populations of the immune systems and thereby represent a direct signaling connection between the CNS and the immune system. My data shows that the C57BL/6 (B6) mouse strain is more susceptible to the parasite than BALB/c mice. Additionally to a significant weight loss upon infection B6 mice also show more drastic changes in neuronal morphology than BALB/c mice. Both strains react strongly microglial activation to T. gondii infection. Interestingly microglial morphology upon infection is strain specific and display different phenotypes. The second part of the data shows that B6 mice lacking the p75 neurotrophin receptor (knock out) show a milder reaction to the T. gondii infection on their neuronal architecture compared to the wild type.