Multiple sclerosis: an altered immune response or an altered stress response?

The pathogenesis of multiple sclerosis (MS), the major neurological disease of young adults in the Western world, is still poorly understood, and no effective therapy to block MS is available as yet. The clinical symptoms of MS result from inflammatory damage to the insulating myelin sheath of axons in the CNS and — at later stages — to axons themselves. A local autoimmune process involving activation of helper T cells against CNS protein components is likely to be crucial in this development. Especially at the first stages of MS, therapies aimed at the selective downregulation of MS-specific autoimmune responses may contribute to controlling the disease. Key to the success of such approaches is the identification of CNS proteins that are the target of local T cell responses. We recently identified the small heat-shock protein B-crystallin as the single immunodominant myelin antigen in MS-affected myelin. This review discusses the functional and therapeutic implications of this finding along with other data on MS, and hypothesizes that an inappropriate stress response within the CNS itself is crucial as an initiating event in disease development.Abbreviations APC Antigen-presenting cells - BBB Blood-brain barrier - EAE Experimental allergic encephalomyelitis - HPLC High-performance liquid chromatography - HSP Heat-shock protein - IFN Interferon - IL Interleukin - MBP Myelin basic protein - MS Multiple sclerosis - TNF Tumor necrosis factor     

Nanoparticle-induced immune response: Health risk versus treatment opportunity?

Nanoparticles (NPs) are not only employed in many biomedical applications in an engineered form, but also occur in our environment, in a more hazardous form. NPs interact with the immune system through various pathways and can lead to a myriad of different scenarios, ranging from their quiet removal from circulation by macrophages without any impact for the body, to systemic inflammatory effects and immuno-toxicity. In the latter case, the function of the immune system is affected by the presence of NPs. This review describes, how both the innate and adaptive immune system are involved in interactions with NPs, together with the models used to analyse these interactions. These models vary between simple 2D in vitro models, to in vivo animal models, and also include complex all human organ on chip models which are able to recapitulate more accurately the interaction in the in vivo situation. Thereafter, commonly encountered NPs in both the environment and in biomedical applications and their possible effects on the immune system are discussed in more detail.Not all effects of NPs on the immune system are detrimental; in the final section, we review several promising strategies in which the immune response towards NPs can be exploited to suit specific applications such as vaccination and cancer immunotherapy.     

Serum lipoproteins: Trojan horses of the immune response?

T cells recognizing lipid antigens presented by CD1 molecules have an important role in the immune response. Several lipid antigens for CD1-restricted T cells have been identified, as have some rules of CD1 loading and CD1-restricted presentation. Little is known, however, about the delivery of lipid antigens from either extracellular compartments or CD1-negative cells to CD1-expressing antigen-presenting cells (APCs). A recent study provides evidence for a role for apolipoprotein E in binding lipid antigens and delivering them to APCs.     

Human β-defensin 2 is involved in CCR2-mediated Nod2 signal transduction,leading to activation of the innate immune response in macrophages

Beta-defensins contribute to host innate defense against various pathogens, including viruses, although the details of their roles in innate immune cells are unclear. We previously reported that human β-defensin 2 (HBD 2) activates primary innate immunity against viral infection and suggested that it plays a role in the induction of the adaptive immune response. We analyzed the mechanisms by which HBD 2 primes innate antiviral immunity and polarized activation of macrophage-like THP-1 cells using the receptor-binding domain (RBD) of Middle East respiratory syndrome coronavirus (MERS-CoV) spike protein (S RBD) as a model antigen. The expression of nucleotide-binding oligomerization domain containing 2 (Nod2), type I interferons, (IFNs), and proinflammatory mediators was enhanced in S RBD-HBD 2-treated THP-1 cells. S RBD-HBD 2 treatment also enhanced phosphorylation and activation of receptor-interacting serine/threonine-protein kinase 2 and IFN regulatory factor 3 compared to S RBD alone. Finally, HBD 2-conjugated S RBD interacted with C-C chemokine receptor 2 (CCR2), and Nod2 was involved in HBD 2-mediated CCR2 signaling, which was associated with the activation and M1 polarization of THP-1 cells. Therefore, HBD 2 promotes CCR2-mediated Nod2 signaling, which induces production of type I IFNs and an inflammatory response, and enhances primary innate immunity leading to an effective adaptive immune response to HBD 2-conjugated antigen.     

A case for immune response genes?

Diabetes is not a single disease. Some patients develop insulin deficiency fairly rapidly and these are usually young, have lymphocytic infiltration of their pancreatic islets, possess circulating islet-cell antibody, and show a strong association with certain HLA phenotypes. This form of the disease is designated type I (juvenile onset or insulin-dependent diabetes mellitus, IDDM). The key factors involved in its pathogenesis were recently reviewed at the fourth of a series of international meetings on the immunology of diabetes'. This meeting was held in memory of Andrew Cudworth whose standing was pre-eminent in the immunogenetics of diabetes and whose untimely death is keenly felt.     

Allergy immunotherapy and inhibition of Th2 immune responses: a sufficient strategy?

Th2 immune responses mediated by the secretion of IL-4, IL-5 and IL-13 are key in the pathogenesis of atopic disorders, including allergen-induced asthma, rhinoconjunctivitis and anaphylaxis. Although such responses are downregulated to some degree by conventional specific immunotherapy, this approach is only partially effective and has a substantial risk of adverse effects. Many strategies for immunotherapeutic prophylaxis and for treatment of atopic diseases have been devised on the basis of mouse allergy and autoimmune models, including the downregulation of Th2 responses by the induction of regulatory T cell activity, Th2 to Th1 immune deviation, Th1 crossregulation of Th2 immune responses, anergy and immunosuppressive cytokines. The blockade of events that are not allergen-specific, such as T cell costimulation and downstream events dependent on IgE, cytokines and chemokines, has also been pursued. With the exception of monoclonal antibody therapy for the blockade of IgE effector function, the application of most of these strategies to humans is at an early stage. Whether the inhibition of Th2 responses without concurrent downregulation of Th1 responses will be sufficient for allergic immunotherapy, particularly for atopic dermatitis and asthma, is an important but unresolved issue.     

Host immune response in B-cell lymphomas: friend or foe?

The interaction of B-cell malignancies with the host immune system is a dynamic and bilateral process. Certain lymphomas more commonly arise within a background of autoimmunity or chronic infection. Initiation of these tumors is commonly reliant on antigenic stimulation and/or T-cell help. Apart from its tumor-fueling role, the host immune response plays a critical role in cancer immunosurveillance and immunoediting. The concept of immunoediting holds that the immune system sculpts the tumor's immunogenicity in a dynamic process that involves three essential phases: elimination, equilibrium, and escape. Data obtained by studying gene-targeted animals and human lymphomas that support the critical role of the immune response in the initiation, progression, and immunoediting of lymphoid malignancies are summarized here. A thorough understanding of this interaction will lead to the identification of more rational treatment targets and improved immunotherapies in B-cell lymphomas.     

The 'danger' sensors that STOP the immune response: the A2 adenosine receptors?

Immune cells not only destroy pathogens but might also cause collateral injuries to normal tissues. The surprisingly low incidence of post-inflammatory complications is explained here by a 'danger-sensing' physiological mechanism that ensures the tissue-protecting negative feedback inhibition of overactive immune cells. We focus here on immunoregulatory influences of 'non-immune' signaling molecules in physiological and pathophysiological tissue microenvironments. We propose that hypoxia-associated accumulation of extracellular adenosine might be an important immunoregulatory signal. A2 receptors for extracellular adenosine might act as both primary sensors of excessive collateral tissue damage during an immune response and triggers of the emergency downregulation of overactive immune cells. Regulation by extracellular adenosine would protect normal organs from injury and/or re-direct immune responses.     

Th1 and Th2 subsets: paradigms lost?

The T helper 1 (Th1)/Th2 model has provided a valuable framework to investigate and explain many immune reactions and now pervades current thinking on the regulatory role of T cells. However, individual T cells and clones display remarkable diversity in their cytokine profiles, collectively forming a continuous spectrum in which Th1 and Th2 cells may be only two of the possible extreme phenotypes. For these reasons, Anne Kelso argues that cytokine-producing T cells cannot be classified into discrete subsets.     

Exercise and the immune system: a model of the stress response?

Exercise influences natural immunity, T- and B-cell functions, and cytokine responses, through circulatory (hemodynamic) changes and by endocrine hormones secreted in response to physical stress. The magnitude of the effects on the immune system reflects the intensity, duration and chronicity of the exercise. In this review, Laurie Hoffman-Goetz and Bente KlarlundPedersen suggest that exercise-immune interactions can be viewed as a subset of stress immunology.     

Glomerulonephritis,Th1 and Th2: what's new?

Glomerulonephritis (GN), the major worldwide cause of chronic renal disease and renal failure, shows a wide spectrum of histological patterns, severity of injury and clinical outcomes that may be related to the nature of the nephritogenic immune response. In the majority of cases, there is evidence of a central role for cognate immunity in the initiation of human GN and contributions of both humoral and cellular effector mechanisms have been demonstrated in both humans and in animal models. T helper cell subsets are known to activate different immune effector mechanisms which influence disease outcomes in infectious and autoimmune diseases and evidence is now accumulating that Th1 and Th2 subsets direct diverging effector pathways that lead to different patterns and severity of glomerular injury in GN. Th1-predominant responses appear to be associated strongly with proliferative and crescentic forms of GN that result in severe renal injury, while Th2 responses are associated with membranous patterns of injury. The challenge remains to understand fully the relevance of T helper cell subset responses to the spectrum of human GN and to apply this new knowledge to the development of more potent and selective therapeutic strategies.     

Serum HLA class I antigens: markers and modulators of an immune response?

HLA class I antigens circulate in the serum in soluble form. This article discusses the clinical significance of levels of serum HLA class I antigens, both in patients with viral diseases and following organ transplantation, as well as the potential involvement of such antigens in the immune response.