Desmoglein autoimmunity in the pathogenesis of pemphigus

Cigarette smoking is one of many environmental exposures, including infectious agents, silica exposure, hormonal and dietary factors, hypothesized to be linked to the development of SLE. Cigarette smoke contains hundreds of potentially toxic components, including tars, nicotine, carbon monoxide, polycyclic aromatic hydrocarbons among others. Whether cigarette smoking increases the risk of developing SLE remains controversial. To date, three case-control studies have reported significantly increased odds ratios for the development of SLE in smokers, while six others have not found a clear association. A meta-analysis statistically combining the effect estimates from the available studies, revealed a modestly increased risk posed by current smoking (RR 1.5 [95% CI 1.09, 2.08]), but no increased risk associated with past smoking. The strengths and weaknesses of these data and potential implications are discussed.     

Desmoglein autoimmunity in the pathogenesis of pemphigus

The most characteristic feature of pemphigus is a loss of cohesion between keratinocytes, resulting in formation of blisters and erosions on the mucosal membranes and the skin. Identification of circulating antibodies which bind to desmogleins (Dsg), transmembrane proteins involved in assembly of the desmosomes, led to the immediate realization that these antibodies may be pathogenic by interfering with desmosomal function. Despite extensive experimental evidence documenting the presence of the anti-Dsg response, its pathogenic relevance is still debated. At the current stage of the knowledge it seems likely that anti-Dsg imunoglobulins may play a role in pemphigus via interference with cellular Dsg trafficking and by activation of specific signalling pathways rather than by simple interference with desmosomal adhesion.     

Virus infection,antiviral immunity,and autoimmunity

As a group of disorders, autoimmunity ranks as the third most prevalent cause of morbidity and mortality in the Western World. However, the etiology of most autoimmune diseases remains unknown. Although genetic linkage studies support a critical underlying role for genetics, the geographic distribution of these disorders as well as the low concordance rates in monozygotic twins suggest that a combination of other factors including environmental ones are involved. Virus infection is a primary factor that has been implicated in the initiation of autoimmune disease. Infection triggers a robust and usually well-coordinated immune response that is critical for viral clearance. However, in some instances, immune regulatory mechanisms may falter, culminating in the breakdown of self-tolerance, resulting in immune-mediated attack directed against both viral and self-antigens. Traditionally, cross-reactive T-cell recognition, known as molecular mimicry, as well as bystander T-cell activation, culminating in epitope spreading, have been the predominant mechanisms elucidated through which infection may culminate in an T-cell-mediated autoimmune response. However, other hypotheses including virus-induced decoy of the immune system also warrant discussion in regard to their potential for triggering autoimmunity. In this review, we discuss the mechanisms by which virus infection and antiviral immunity contribute to the development of autoimmunity.     

Parasitic infection and autoimmunity

The studies summarized in this paper indicate that parasitic infections can serve as a trigger factor of autoimmune reactivity by several mechanisms. The relationship between parasites and autoimmunity could be manifested by the presence of autoantibodies or T-cells with autoreactivity. In spite of the evidence that has accumulated, the specific association between infection and autoimmunity is still obscure. The reasons for tissue damage in parasitic diseases are controversial. Some believe it is the result of pathogenic autoantibodies or autoreactive T-cells. Others argue against the causative role of autoimmunity in the formation of tissue lesions. The parasite itself could be the cause of tissue destruction, thus releasing high amounts of self antigens which might stimulate the autoreactivity. There is now little doubt that some degree parasite/host cross-reactivity occurs, and definition of cross-reacting antigens and epitopes is now taking place. It seems likely that a combination of events could result in cross-reactivity including: parasites themselves have cross reactive molecules and altered self antigens by adsorbing of parasite material to surrounding host cells. The mechanisms involved in parasites autoimmunity are complex and numerous, requiring a rigorous experimental approach to rationalize each step and determine its clinical importance. The developed methods in immunochemistry, monoclonal antibodies and hybridoma technology, and recombinant DNA research not only facilitate this kind of approach but also allow optimism for a successful outcome.     

Cryptic infection and autoimmunity

Infection as an environmental factor in autoimmunity has long been recognized. Numerous examples can be found in which pathogens express antigens that cross-react with host antigens or induce local inflammatory responses that can lead to autoimmune responses through a very complex set of circumstances. Borrowing from the relationship between chronic infection with hepatitis C virus and autoimmune hepatitis as an example, we consider the possibility that infection with an unknown virus having specific tissue tropism could lead to a perceived autoimmune process. We raise the question whether such should be considered for Type 1 diabetes.     

Tertiary lymphoid organs in infection and autoimmunity

The lymph nodes (LNs) and spleen have an optimal structure that allows the interaction between T cells, B cells and antigen-presenting dendritic cells (DCs) on a matrix made up by stromal cells. Such a highly organized structure can also be formed in tertiary lymphoid organs (TLOs) at sites of infection or chronic immune stimulation. This review focuses on the molecular mechanisms of TLO formation and maintenance, the controversies surrounding the nature of the inducing events, and the functions of these structures in infection, transplantation and autoimmunity.     

Alternatively activated macrophages in infection and autoimmunity

Macrophages are innate immune cells that play an important role in activation of the immune response and wound healing. Pathogens that require T helper-type 2 (Th2) responses for effective clearance, such as parasitic worms, are strong inducers of alternatively activated or M2 macrophages. However, infections such as bacteria and viruses that require Th1-type responses may induce M2 as a strategy to evade the immune system. M2 are particularly efficient at scavenging self tissues following injury through receptors like the mannose receptor and scavenger receptor-A. Thus, M2 may increase autoimmune disease by presenting self tissue to T cells. M2 may also exacerbate immune complex (IC)-mediated pathology and fibrosis, a hallmark of autoimmune disease in women, due to the release of profibrotic factors such as interleukin-1β, transforming growth factor-β, fibronectin and matrix metalloproteinases. We have found that M2 comprise anywhere from 30% to 70% of the infiltrate during acute viral or experimental autoimmune myocarditis, and shifts in M2 populations correlate with increased IC deposition, fibrosis and chronic autoimmune pathology. Thus, women may be at an increased risk of M2-mediated autoimmunity due to estrogen's ability to increase Th2 responses.     

Regulation of allergy and autoimmunity in helminth infection

Parasitic infections are a major theme in the "hygiene hypothesis", as allergies and autoimmune diseases are less prevalent in countries with higher burdens of helminths and other parasitic organisms. Helminths"-the grouping of multicellular worm parasites including nematodes, cestodes and trematodes-tend to establish long-lived, chronic infections indicating successful down-modulation of the host immune system. In this review, we describe the intricate immunology of host-helminth interactions and how parasites manipulate immune responses to enhance their survival. In so doing, they often minimise immunopathology and, it is suggested, reduce host susceptibility to, and severity of allergic and autoimmune diseases. Studies on helminth-infected communities and individuals support the hypothesis that an immuno-regulatory network promoted by parasites extends its influence to limiting allergies. Experimental models are now probing more deeply into the area of immune modulation by helminths, and we discuss the likely mechanisms by which helminths could be establishing a strongly regulatory environment. Understanding and harnessing the modulatory capacity of helminths may uncover novel therapeutic interventions, mimicking and exploiting their evolution for our benefit. Parasitic infections are a major theme in the-"hygiene hypothesis", as allergies and autoimmune diseases are less prevalent in countries with higher burdens of helminths and other parasitic organisms. Helminths"-the grouping of multicellular worm parasites including nematodes, cestodes and trematodes-tend to establish long-lived, chronic infections indicating successful down-modulation of the host immune system. In this review, we describe the intricate immunology of host-helminth interactions and how parasites manipulate immune responses to enhance their survival. In so doing, they often minimise immunopathology and, it is suggested, reduce host susceptibility to, and severity of allergic and autoimmune diseases. Studies on helminth-infected communities and individuals support the hypothesis that an immuno-regulatory network promoted by parasites extends its influence to limiting allergies. Experimental models are now probing more deeply into the area of immune modulation by helminths, and we discuss the likely mechanisms by which helminths could be establishing a strongly regulatory environment. Understanding and harnessing the modulatory capacity of helminths may uncover novel therapeutic interventions, mimicking and exploiting their evolution for our benefit.     

Regulation of inflammation, autoimmunity, and infection immunity by HVEM-BTLA signaling

The HVEM, or TNFRSF14, is a membrane-bound receptor known to activate the NF-κB pathway, leading to the induction of proinflammatory and cell survival-promoting genes. HVEM binds several ligands that are capable of mediating costimulatory pathways, predominantly through its interaction with LIGHT (TNFSF14). However, it can also mediate coinhibitory effects, predominantly by interacting with IGSF members, BTLA or CD160. Therefore, it can function like a "molecular switch" for various activating or inhibitory functions. Furthermore, recent studies suggest the existence of bidirectional signaling with HVEM acting as a ligand for signaling through BTLA, which may act as a ligand in other contexts. Bidirectional signaling, together with new information indicating signaling in cis by cells that coexpress HVEM and its ligands, makes signaling within a HVEM-mediated network complicated, although potentially rich in biology. Accumulating in vivo evidence has shown that HVEM-mediated, coinhibitory signaling may be dominant over HVEM-mediated costimulatory signaling. In several disease models the absence of HVEM-BTLA signaling predominantly resulted in severe mucosal inflammation in the gut and lung, autoimmune-like disease, and impaired immunity during bacterial infection. Here, we will summarize the current view about how HVEM-BTLA signaling is involved in the regulation of mucosal inflammation, autoimmunity, and infection immunity.     

Mannose-binding lectin: clinical implications for infection, transplantation, and autoimmunity

Mannose-binding lectin (MBL) is a recognition molecule of the lectin pathway of complement and a key component of innate immunity. MBL variant alleles have been described in the coding region of the MBL gene, which are associated with low MBL serum concentration and impaired MBL structure and function. Both high and low serum levels of functional MBL have been associated with a variety of diseases and disease complications. Functioning as double-edged sword, low MBL serum levels have been shown to enhance the risk for infections. On the other hand, high MBL serum levels and high MBL activity have been associated with inflammatory diseases, transplant rejection, and diabetic nephropathy. Underscoring the Jekyll-and-Hyde character of MBL, both high and low serum MBL levels are associated with several aspects of autoimmune diseases. This review provides a general outline of the genetic and molecular characteristics of MBL and discusses MBL-disease association and its consequence in infection, transplantation, and autoimmunity.     

Involvement of semaphorins in autoimmunity]

Semaphorins were identified originally as guidance cues for developing axons. However, it is becoming clear that several semaphorins are crucially involved in the immune system. For instance, Sema4D (CD100) enhances activation of B cells and dendritic cells, and Sema4A is involved in T cell priming and Th1/Th2 regulation. In addition, recent cumulative evidence reveals their importance in immunological homeostasis. We here focus on our current understanding of the roles of semaphorins in autoimmunity.     

The viral enterprises in autoimmunity: conversion of target cells into de novo APCs is the presage to autoimmunity

An autoimmune disease (AD) occurs in a situation where an individual's protective immune system attacks and destroys the individual's own tissues and organ(s), causing a recognizable syndrome(s). The viruses feature in the triggering of autoimmune diseases in genetically primed individuals through generating a viral group of regulatory immediate early proteins (IE). The IE indulges in promiscuous regulations of the viral replications as well as of host intracellular proteins. But there are consequences in the IE controlling host cell protein regulations, which we suggest as: the IE titration of the transactivator protein, autoimmune regulator (AIRE), which causes abolition of central tolerance; and the IE titration of the repressor protein, FOXP3, which results in the breach of peripheral tolerance. Titrations of AIRE and FOXP3 allow the escape of autoreactive T cells into the (peripheral) circulation where they can reach and zero in on self-tissues. The AD-predisposing MHC-II-DR-DQ haplotypes probably play a crucial role in the shaping of the T cell repertoire intrathymically for the survival of budding autoreactive T cell receptors (TCRs). Finally, we suggest there is IE titration of the repressors, the histone deacetylases (HDACs), in target organ cells which then consequentially express de novo MHC-II molecules and become de novo non-professional antigen-presenting cells (APCs), able to present viral peptides to cognate TCRs, thereby enrolling themselves for apoptotic death: a destiny of all APCs in immune responses, in general. Extensive apoptotic destruction of organ cells leads to an autoimmune syndrome(s).     

Vimentin as antigenic target in autoimmunity: A comprehensive review

Vimentin is a protein of intermediate filament family, which is expressed in all mesenchymal cells. Vimentin plays a key role in the physiology of the cell, cellular interactions and the functioning of the immune system. Post-translationally modified and native forms of vimentin are involved in the pathogenesis of inflammation and many autoimmune diseases: rheumatoid arthritis, sarcoidosis, systemic lupus erythematosus, antiphospholipid syndrome, Crohn's disease, ankylosing spondyloarthritis and idiopathic pulmonary fibrosis. Modifications of the protein lead to the formation of antigenic epitopes and, as a result, to the synthesis of antibodies. Citrullinated, carbamylated and acetylated forms of vimentin participate in the pathogenesis of RA, and antibodies against them serve as diagnostic and prognostic markers of the disease. Epitopes of native vimentin are antigenic in the group of HLA-DRB1*0301 positive patients with sarcoidosis. In addition, vimentin takes part in pathogenesis of tubulointerstitial inflammation and glomerulonephritis in lupus. In antiphospholipid syndrome interactions of vimentin and cardiolipin on the surface of apoptotic cells lead to the formation of an immunogenic complex. Antibodies against vimentin/cardiolipin complex are involved in the mechanism of thrombogenesis and serve to identify patients seronegative for antibodies to cardiolipin and ß2glycoprotein-I with the clinical features. Post-translationally modified form of the protein is citrullinated and MMP-degraded vimentin, which was found in serum of patients with Crohn's disease and ankylosing spondyloarthritis.