Current Immunology Reviews (Discontinued) - Volume 9, Issue 4, 2013

Myasthenia gravis (MG), an autoimmune neuromuscular junction disorder characterized by fatigable weakness of voluntary muscles including ocular, facial, oropharyngeal, limb and respiratory muscles with a prevalence of about 150-200 per million, is a disease of the postsynaptic neuromuscular junction where acetylcholine receptors (AChRs) are targeted by autoantibodies in 80-85% of MG patients. We face unresolved issues in the efforts to clarify the pathogenesis of remaining MG patients (seronegative MG). In this regard, we have paied attention to the findings that part of seronegative MG patients have antibodies against other postsynaptic proteins: the muscle-specific tyrosine kinase (MuSK) which is activated by Dok-7 (muscle adaptor protein) and plays a key role in AChR clustering at the end-plate membrane, and the low-density lipoprotein receptor-related protein 4 (Lrp4) which is the agrin receptor and mediates the neural signal to MuSK. To search a clue to further understanding of the immunopathological mechanisms underlying postsynaptic junction disorders, we need to understand a complex architecture formed by diversity of elements through signals orchestrated by sophisticated interactions in the synapse. The present review focuses on the signaling downstream from MuSK which is originated from the activation by agrin/Lrp4 signaling (via MuSK immunoglobulin-like domains 1 and 2) and by Wnt signaling (via MuSK cysteine-rich domain (CRD)), and also focuses on the synaptic stability by extracellular matrix proteins (such as collagen Q, perlecan and biglycan) and their receptors (via dystroglycans). Also, the review may shed light on possible mechanisms (including Wnt/MuSK CRD, Lrp4 and laminin-network) to modify the presynaptic function in autoimmune postsynaptic disorders.

Type II innate lymphoid cells (ILC2) are a novel population of lineage-negative cells that produce high levels of Th2 cytokines IL-5 and IL-13. ILC2 are found in human respiratory and gastrointestinal tissue as well as in skin. Studies from mouse models of asthma and atopic dermatitis suggest a role for ILC2 in promoting allergic inflammation. The epithelial cytokines IL-25, IL-33, and TSLP, as well as the lipid mediator leukotriene D4, have been shown to potently activate ILC2 under specific conditions and supporting the notion that many separate pathways in allergic disease may result in stimulation of ILC2. Ongoing investigations are required to better characterize the relative contribution of ILC2 in allergic inflammation as well as mechanisms by which other cell types including conventional T cells regulate ILC2 survival, proliferation, and cytokine production. Importantly, therapeutic strategies to target ILC2 may reduce allergic inflammation in afflicted individuals. This review summarizes the development, surface marker profile, cytokine production, and upstream regulation of ILC2, and focuses on the role of ILC2 in common allergic diseases.

Systemic lupus erythematosus (SLE) is a complex multi-organ autoimmune disease, the pathogenesis of which is still not deciphered. The neutrophil, an innate immune cell critical in controlling infections, has traditionally not been regarded as a contributor to systemic autoimmunity due to its lack of specificity and short lifespan. Many recent findings have instead shown that these cells have a role in regulating the adaptive as well as the innate immune response, and that they may play a key role in the abnormal responses seen in SLE. Neutrophils can secrete various cytokines and cellular mediators that can regulate both innate and adaptive arms of immunity, and may serve as a source of immunogens that may trigger and reinforce autoimmunity. In the present review we will discuss the relevance of neutrophil functions and neutrophil regulation of the immune response in the context of SLE.

Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening disease of immune regulation, clinically characterized by prolonged fever, cytopenias and hepatosplenomegaly. Low or absent natural killer (NK) cell and CD8+ cytotoxic T lymphocyte (CTL) cytotoxicity is one of the hallmarks of HLH. This results in ineffective infection control leading to prolonged and excessive activation of antigen presenting cells (macrophages, histiocytes) and multisystem inflammation. HLH may occur as a primary (genetic) condition due to mutations in genes important in the pathway of granule mediated cytotoxicity or as a secondary condition wherein identical clinical findings may arise secondary to infectious, rheumatological, malignant, or metabolic conditions. Primary HLH is further divided into familial HLH (FHL), in which HLH is often the presenting clinical manifestation of disease, and other genetic causes in which HLH is one of several clinical manifestations. Five different forms of FHL have so far been described; Type 1 is due to yet unidentified gene defect located on chromosome nine. Type 2 is caused by mutations in the perforin (PRF1) gene (20-40% of all FHL cases), type 3 by mutations in the Munc- 13–4 (UNC13D) gene (20-25% of all FHL cases), type 4 by mutations in the syntaxin 11 (STX11) gene (14-21% of all FHL cases) and the recently described type 5 due to mutations in the gene encoding syntaxin binding protein 2 (STXBP-2). The incidence of the five types varies significantly in different ethnic groups. Early diagnosis and initiation of immunosuppressive therapy is extremely important due to the life threatening nature of this disease. There is no single diagnostic test available for HLH and it is based on constellation of clinical manifestations and laboratory parameters which often overlap with those of severe infection and sepsis. Identification of patients with primary HLH and their underlying genetic defects require specialized laboratory tests and is important for predicting relapse and planning early therapeutic hematopoietic stem cell transplantation (HSCT). This review will focus on the pathophysiology of HLH with emphasis on FHL, clinical manifestations, diagnostic approach for rapid identification of genetic defects and important management issues.

The communication between the immune and central nervous systems has been known for decades. Although the biological rules and complexity of the neuroimmune axis is yet to be clarified, in the modern era of immunology and clinical neurosciences it has become a dynamically evolving paradigm. In this review we trace the major findings of this emerging field with a special focus on innate immune cells and their phylogenetically conserved receptors, in line with their role in various psychiatric and neurological diseases. A particular interest will be given to monocytes, macrophages/microglia, dendritic cells, Toll-like and RIG-I-like receptors as well as their contribution to inflammation and other pathological processes in the CNS. Uncovering immunological mechanisms in the context of brain functions emerges as a promising avenue for future therapeutic interventions in various, still incurable ailments such as Alzheimer’s disease, schizophrenia, or different mood disorders such as major depression or bipolar disorder. We propose new perspectives for the pharmacological modification of innate immune cells and their response to inflammatory cues in the brain. A holistic concept of studying the gut-brain-immune triangle is also suggested to bring up novel approaches in immunology, gastroenterology, psychiatry and neurology.

Atopy is characterized by a high production of IgE in response to common allergens exposure and by positive responses to skin-prick test against specific antigens. Atopy can contribute to the development of atopic asthma and atopic eczema. This condition involves the participation of different cells including mast cells that express the high-affinity Fc receptor for IgE, the FcεRI receptor. Crosslinking of FcεRI-bound IgE in absence of an allergen increases the expression of IgE receptor, enhances mast cells survival and induces synthesis and secretion of several inflammatory mediators that contribute to increase allergic reactions. The number of mast cells and their mediators increase in asthma and eczema and could be involved in the pathogenesis of these diseases. Genetic factors such as mutations and polymorphism in several genes of the subunits of the FcεRI (receptor for IgE), cytokines and their receptors (IL-4, IL-13), and transcription factors (STAT6) allow IgE synthesis. Moreover, epigenetic regulation of genes such as DNA methylation and histone modifications are the genetic background of atopy. This review attempts to summarize the recent progress on the pathology of atopy, its risk factors and the role of mast cells in two atopic diseases: atopic asthma and atopic eczema.

The molecular basis for obtaining novel anti-malarial vaccine candidates depends on a considered selection of antigenic peptides, mainly derived from Plasmodium antigens’ non-polymorphic regions. Since such targeted-molecules are poorly immunogenic when tested as vaccine components, they usually have to be modified to overcome their immunological phenotype. Transition state theory, explaining how peptidases catalyse a given peptide bond breakage, thus led to reduced amide pseudopeptides being proposed as possible mimetics for a transition-state. Stabilising such high-energy molecular stages could become a strategy for inducing antibodies potentially harbouring catalytic properties. Hence, isostere-bond peptido-mimetics represented a rational choice as potential abzyme-inducers and site-directed designed reduced amide pseudopeptides for obtaining peptide-analogues from selected malarial high-binding motifs. This novel family of vaccine candidates has proved to be an efficient functional antibody-inducer, the latter acting as efficient blockers of Plasmodium infection of human and mouse RBCs.