Current Immunology Reviews (Discontinued) - Volume 11, Issue 2, 2015

Intracerebral hemorrhage (ICH) is a deadly subtype of stroke that occurs when an arteriole ruptures and bleeds into the brain parenchyma. There is no specific treatment for ICH and progress has not been made to reduce mortality rates or improve outcomes. The immune response is a key component of secondary injury after ICH and represents an accessible treatment target, as it develops over several days. Initiators of this response include the clotting cascade, complement activation, and toll-like receptor-4 activation. These signaling cascades activate brain resident cells, including microglia, astrocytes, and mast cells, which then secrete pro-inflammatory cytokines, chemokines, and free radicals. This response initiates breakdown of the blood-brain barrier and edema formation. Circulating leukocytes migrate into the brain parenchyma by following chemokine gradients and other signals. Once in the brain, neutrophils, monocytes, and T cells induce secondary injury, but may also be important for phagocytosis of the hematoma and later recovery. This article reviews preclinical literature pertaining to these complex immune responses after ICH and provides clinical correlates when available.

Evidence for the tenuous regulation between the immune system and central nervous system (CNS) can be found with examples of interaction between these organ systems gone awry. Multiple sclerosis (MS) is the prototypical inflammatory disease of the CNS and is characterized by widely distributed inflammatory demyelinating plaques that can involve the brain, spinal cord and/or optic nerves. Optic neuritis (ON), inflammatory injury of the optic nerve that frequently occurs in patients with MS, has been the focus of intense study in part given the readily accessible nature of clinical outcome measures. Exploring the clinical and pathological features of ON in relation to other inflammatory demyelinating conditions of the CNS, namely MS and neuromyelitis optica, provides an opportunity to glean common and distinct mechanisms of disease. Emerging data from clinical studies along with various animal models involving ON implicate innate and adaptive immune responses directed at glial targets, including myelin oligodendrocyte glycoprotein and aquaporin 4. Resolution of inflammation in ON is commonly observed both clinically and experimentally, but persistent nerve injury is also one emerging hallmark of ON. One hypothesis seeking evaluation is that, in comparison to other sites targeted in MS, the optic nerve is a highly specialized target within the CNS predisposing to unique immunologic processes that generate ON. Overall, ON serves as a highly relevant entity for understanding the pathogenesis of other CNS demyelinating conditions, most notably MS.

Neuropsychiatric systemic lupus erythematosus (NPSLE) is a clinical syndrome characterized by various neurologic phenotypes in patients with systemic lupus erythematosus (SLE). Mechanisms of NPSLE pathogenesis are not well understood although aberrant activation of both innate and adaptive immune pathways is thought to play a role. Animal models suggest a variety of factors that may instigate these neuropsychiatric events, including production of pathogenic autoantibodies, release of proinflammatory cytokines, disruption of the blood-brain barrier, and dysregulation of innate immune responses.

Stroke is one of the leading causes of death and disability worldwide. The limited utility of current treatments, the increasing rates of stroke survivorship and subsequent long-term disability necessitate novel approaches to improve functional recovery after injury. The underlying immune mechanisms mediating inflammation and subsequent repair beyond the acute phase of injury remain understudied. The relative balance of injury and repair is dependent in part on the polarization state of microglia, the resident tissue macrophage of the central nervous system. Microglia can be classically activated to a pro-inflammatory phenotype, or alternatively activated to an immunomodulatory, tissue repair phenotype depending on the balance of local environmental cues. Once activated, they orchestrate a complex symphony of inflammation and repair, interacting with both the peripheral immune system and local cells such as astrocytes and neural stem cells to coordinate the resolution of inflammation and repair of damaged tissues. Furthermore, neural stem cells and astrocytes themselves appear to have intrinsic immunomodulatory properties which could be used in the development of future therapies. Enhancing these “reparative” functions with pharmacologic agents could open up exciting new avenues to improve long-term functional recovery in stroke patients.

The inflammatory response is a fundamental driving force in the pathogenesis of Alzheimer’s disease (AD). In the setting of accumulating immunogenic Aß peptide assemblies, microglia, the innate immune cells of the brain, generate a non-resolving immune response and fail to adequately clear accumulating Aß peptides, accelerating neuronal and synaptic injury. Pathological, biomarker, and imaging studies point to a prominent role of the innate immune response in AD development, and the molecular components of this response are beginning to be unraveled. The inflammatory cyclooxygenase-PGE2 pathway is implicated in pre-clinical development of AD, both in epidemiology of normal aging populations and in transgenic mouse models of Familial AD. The cyclooxygenase-PGE2 pathway modulates the inflammatory response to accumulating Aß peptides through actions of specific E-prostanoid G-protein coupled receptors.

Asthma is a chronic inflammatory disease of the airways with distinct features including nonspecific airway hyper-responsiveness, reversible bronchoconstriction, inflammation, and airway remodeling. The classical characteristics of asthma are the activation and recruitment of inflammatory cells, shedding of bronchial epithelium, subepithelial fibrosis, angiogenesis, mucus metaplasia and changes in the mass of airway smooth muscle cells. A complex interaction between environmental and genetic factors contributes to the disease and its heterogeneity. Various cell types, endogenous mediators including cytokines, chemokines, and growth factors contribute to its pathological events. Eosinophils play a dominant role in the disease, however, neutrophils also participate in more severe cases. The chronic inflammation and airway remodeling result from the effects of cytokines on various cell types that participate in the etiology and pathogenesis of the disease. Cytokines bind to their receptors and through multiple signal transduction mechanisms produce the effects. Up to 10% of the patients are refractory to current therapy for asthma. The pathological events in asthma at least in part result from the induction of Mitogen Activated Protein Kinases (MAPK) and their associated cytoplasmic proteins. The MAPK signaling cascades play an important role in the activation of inflammatory cells, and are involved in the immune responses and the lymphocyte development. It has been proposed that the clinical symptoms of asthma are dependent on the immunological as well as tissue based memory resulting in chronic signaling that produces a bistable state. The bistable state explains the persistence of symptoms of asthma between episodes. Sustained extracellular regulated kinase 1/2 (ERK1/2) signaling is an example that is responsible for the tissuebased signaling memory. The aim of this review to discuss the recent developments in understanding the function of MAPK, ERK1/2 and p38, and their cytoplasmic proteins in asthma. This will include the role of MAPK pathways in cell types associated with asthma. Specifically their role in T cells, B cells, macrophages, mast cells, eosinophils, dendritic cells, endothelial cells, epithelial cells, and airway smooth muscle cells will be discussed and the novel concept of bistability in asthma will be described.