Photosensitivity in lupus erythematosus

Lupus erythematosus (LE) is an autoimmune disease which can be triggered by environmental factors such as solar irradiation. It has long been observed that especially ultraviolet (UV) exposure can induce and exacerbate skin lesions in patients with this disease. However, despite the frequency of photosensitivity in LE, the mechanisms by which UV irradiation activates autoimmune responses is only now becoming increasingly unfolded by advanced molecular and cellular biological investigations. Phototesting, according to a standardized protocol with UVA and UVB irradiation has proven to be a valid model to study photosensitivity in various subtypes of LE and to evaluate the underlying pathomechanisms of this disease. Detailed analysis of the molecular events that govern lesion formation in experimentally photoprovoced LE showed increased accumulation of apoptotic keratinocytes and impaired expression of the inducible nitric oxide synthase (iNOS). In the near future, gene expression profiling and proteomics will further increase our knowledge on the complexity of the “UV response” in LE. This review summarizes the current understanding of the clinical and molecular mechanisms that initiate photosensitivity in this disease.     

Photosensitivity,Apoptosis, and Cytokines in the Pathogenesis of Lupus Erythematosus: a Critical Review

The underlying pathomechanisms of lupus erythematosus (LE), a multifactorial autoimmune disease, remain elusive. Due to the clinical evidence demonstrating a clear relationship between ultraviolet (UV) light exposure and skin lesions of LE, photosensitivity has been proven to be an important factor in the pathogenesis of the disease. Standardised photoprovocation with UVA and UVB irradiation has been shown to be a reliable model for evaluating photosensitivity in patients with cutaneous LE (CLE) and analysing the underlying medical conditions of the disease. In this respect, UV irradiation can cause aberrant induction of apoptosis in keratinocytes and contribute to the appearance of excessive apoptotic cells in the skin of CLE patients. Moreover, apoptotic cells that cannot be cleared by phagocytes may undergo secondary necrosis and release proinflammatory compounds and potential autoantigens, which may contribute to the inflammatory micromilieu that leads to formation of skin lesions in the disease. In addition to UV-mediated induction of apoptosis, the molecular and cellular factors that may cause the abnormal long-lasting photoreactivity in CLE include mediators of inflammation, such as cytokines and chemokines. In particular, interferons (IFNs) are important players in the early activation of the immune system and have a specific role in the immunological interface between the innate and the adaptive immune system. The fact that treatment with recombinant type I IFNs (α and β) can induce not only systemic organ manifestations but also LE-like skin lesions provides additional evidence for a pathogenetic role of these IFNs in the disease.     

Immunologic and genetic considerations of cutaneous lupus erythematosus: A comprehensive review

Cutaneous lupus erythematosus (CLE) refers to those subtypes of lupus erythematosus (LE) that have predominantly skin manifestations. Discoid lupus erythematosus (DLE), subacute cutaneous lupus erythematosus (SCLE), LE panniculitis (LEP) and lupus erythematosus tumidus (LET) all fall into the category of CLE. The pathogenesis of CLE is likely multifactorial. UV irradiation has been shown to induce keratinocyte apoptosis. Impaired clearance of apoptotic cells is a potential mechanism for the development of CLE. UV irradiation can also induce externalization of autoantigens such as Ro/SSA, exposing them to circulating autoantibodies. Some drugs have been associated with CLE. Possible mechanisms include stimulation of an immune response through disruption of central tolerance and altered T cell function. T17 cells may also play a role in the pathogenesis of CLE as they have been detected in skin lesions of LE. Treg cells have been found to be decreased in LE lesions, which may contribute to the breakdown of self-tolerance. Epidermal Langerhans cells are reduced in CLE while plasmacytoid DCs are increased in the lesions of CLE, suggesting that DCs may also play an important role in the pathogenesis of CLE. Type I IFN- and TNF-α are both upregulated in lesions of CLE. Other cytokines such as IL-6 and IL-17 are also implicated in the pathogenesis of CLE. Cellular and cytokine networks can be impacted by environmental factors and genetic variations and this can result in an increased risk of developing autoimmune diseases such as CLE.     

Ultraviolet B irradiation induces skin accumulation of plasmacytoid dendritic cells: A possible role for chemerin

Abstract

Photosensitivity represents a common feature for most forms of lupus erythematosus (LE) including cutaneous LE. Skin inflammatory infiltrates in response to ultraviolet (UV) exposure are closely involved in the development of skin lesions of LE patients. Skin-infiltrating plasmacytoid dendritic cells (pDCs), considered as a hallmark of cutaneous LE, contribute to its pathogenesis via the production of type I interferons (IFNs). Chemerin, a recently identified chemoattractant for pDCs through its functional receptor chemR23, was found to be elevated in skin lesions of LE patients. The aim of this study was to investigate the effect of UVB irradiation on skin pDC recruitment and chemerin expression. We found that UVB irradiation induced a rapid but transient influx of pDCs as well as a persistent infiltration of neutrophils and macrophages in the mouse skin. The mRNA expression levels of IRF-7, IFN-α and chemR23 were increased in UVB-irradiated skin. Furthermore, UVB irradiation up-regulated skin chemerin production and pDC accumulation in parallel, both of which reached their peaks simultaneously (24?h post-irradiation). Dermal fibroblasts seemed to be the major source of chemerin as evidenced by significantly increased chemerin secretion by UVB-irradiated dermal fibroblasts. More importantly, LE-prone MRL/lpr mouse exhibited greatly increased skin pDC accumulation and chemerin production in response to UVB irradiation, indicating their contributions to increased susceptibility of photosensitivity in the MRL/lpr mouse. Thus, our findings demonstrated that elevated chemerin expression positively correlates with pDC accumulation in UVB-irradiated skin, suggesting a role of chemerin in mediating skin recruitment of pDCs in response to UVB exposure.     

Susceptible cytotoxicity to ultraviolet B light in fibroblasts and keratinocytes cultured from autoimmune-prone MRL/Mp-lpr/lpr mice

The MRL/Mp-lpr/lpr (MRL/l) mouse is an autoimmune model of spontaneous lupus erythematosus (LE), in addition to lupus nephritis. In order to better understand the mechanisms of photosensitivity in LE, in vitro photocytotoxicity was examined by using fibroblasts and keratinocytes cultured from MRL/l mice, control MRL/Mp- +/+ (MRL/n) mice, and normal BALB/c mice. A colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and the acridine orange/ethidium bromide assay were used for determination of cytotoxicity. Fibroblasts cultured from newborn MRL/l mice showed higher susceptibility to single ultraviolet light B (UVB) light irradiation at a dose of 100-500 mJ than those from MRL/n, F1 hybrid of (MRL/l x MRL/n mice), and BALB/c mice. However, the susceptibility to UVB was not observed in young (1-month-old) and adult (4-month-old) MRL/l mice. UVA light irradiation was not cytotoxic. Keratinocytes cultured from MRL mice showed lower cytotoxicity to UVB irradiation than fibroblasts cultured. However, keratinocytes from newborn MRL/l mice showed higher cytotoxicity to 50 mJ UVB irradiation than cells from MRL/n mice. Syngeneic or allogeneic sera augmented UVB-induced cytotoxicity of fibroblasts cultured. UVB irradiation of spleen cells induced no significant difference of cytotoxicity between MRL/l and MRL/n mice. Based on the results of F1 hybrid of (MRL/l x MRL/n) mice, the susceptibility seemed to be associated with autoimmune traits and to be regulated by genetical background.     

Animal models of spontaneous and drug-induced cutaneous lupus erythematosus

Skin lesions are one of the most common manifestations of lupus erythematosus (LE) disorders such as systemic LE and discoid LE. The etiology of cutaneous LE is not fully understood. To address this issue, appropriate animal models frequently clarify the etiology and pathogenesis of autoimmune diseases, although no single animal model perfectly mimics a human disease. A common dermatological finding in many SLE-prone mouse strains is the deposition of immunoglobulins at the dermoepidermal junction. Over the past decade, the most exciting and important finding has been the discovery of the Fas-defect in the pathogenesis of the autoimmune MRL/lpr mouse, which is a good model for the spontaneous development of skin lesions similar to those seen in human LE. The analysis of MRL/lpr mice showed a close association between immunoglobulin deposits and the appearance of skin lesions. Transgenic and knock out mice have advanced the investigation of cutaneous LE. Furthermore, the model of drug-induced cutaneous LE can yield additional insight since the trigger is clear in drug-induced LE. Cutaneous LE lesions can also be induced in TCRalpha-/- mice treated with fluorouracil and ultraviolet B light irradiation. Studies on both spontaneous and experimental models will elucidate the pathogenesis of complicated and multifactorial cutaneous LE.     

Subacute cutaneous lupus erythematosus: 25-year evolution of a prototypic subset (subphenotype) of lupus erythematosus defined by characteristic cutaneous, pathological, immunological, and genetic findings

Subacute cutaneous lupus erythematosus (SCLE) represents a widespread, photosensitive, nonscarring, nonindurated form of lupus erythematosus (LE)-specific skin disease. SCLE lesions are associated with a distinctive immunogenetic background including the production of Ro/SS-A autoantibodies. Individuals who have SCLE skin lesions as a component of their presenting illnesses represent a distinctive subset (subphenotype) of LE that enjoys a good prognosis with respect to life-threatening systemic manifestations of LE. SCLE skin lesions can be triggered by a number of different drugs the majority of which are capable of producing photosensitivity drug reactions in nonlupus patients. Single agent or combination aminoquinoline antimalarial therapy will suffice for 75% of SCLE patients. The remaining 25% will require other forms of systemic antiinflammatory therapy (e.g., diaminodipenylsulfone (Dapsone), thalidomide) or systemic immunosuppressive-immunomodulatory therapy. The etiopathogenesis of SCLE skin lesions is thought to result from four sequential stages: (1) inheritance of susceptibility genes (HLA 8.1 ancestral haplotype [C2, C4 deficiency, TNF-alpha-308A polymorphism], C1q deficiency); (2) loss of tolerance/induction of autoimmunity (ultraviolet light, photosensitizing drugs/chemicals, cigarette smoking, infection, psychological stress); (3) expansion/maturation of autoimmune responses (high levels of autoantibodies (Ro/SS-A), immune complexes, autoreactive T-cells); and (4) tissue injury/disease induction resulting from various autoimmune effector mechanisms (e.g., direct T cell-mediated cytotoxicity, antibody-dependent cell-mediated cytotoxicity).     

Cutaneous histopathology of lupus erythematosus

Lupus erythematosus (LE) is an autoimmune connective tissue disease whose precise aetiological basis is at present uncertain, in which the clinical presentations range from a skin rash unaccompanied by extracutaneous stigmata to one comprising progressive multisystem disease. Recent advances in our understanding of the pathophysiological basis of LE bring hope for novel therapeutic approaches. Essential to a logical therapeutic strategy is accurate diagnosis and subclassification. With respect to the foregoing, a thorough knowledge of clinical manifestations and serology is essential. A skin biopsy for routine histology, as well as the application of direct immunofluorescence microscopy to lesional and/or non-lesional skin, can be a powerful adjunct both to diagnosis and subclassification. From a clinical standpoint, the disease may be classified into systemic (acute), subacute cutaneous and discoid (chronic) forms, all of which have specific correlative cutaneous histopathology which calls to mind a distinct set of histological mimics. There are other, less common, variants of LE, each with its own specific histological differential diagnoses. The cutaneous histopathology that correlates with the traditional forms of LE, along with certain of the novel subtypes, are the subject of this review.     

Molecular mimicry as a mechanism of autoimmune disease

A variety of mechanisms have been suggested as the means by which infections can initiate and/or exacerbate autoimmune diseases. One mechanism is molecular mimicry, where a foreign antigen shares sequence or structural similarities with self-antigens. Molecular mimicry has typically been characterized on an antibody or T cell level. However, structural relatedness between pathogen and self does not account for T cell activation in a number of autoimmune diseases. A proposed mechanism that could have been misinterpreted for molecular mimicry is the expression of dual T cell receptors (TCR) on a single T cell. These T cells have dual reactivity to both foreign and self-antigens leaving the host vulnerable to foreign insults capable of triggering an autoimmune response. In this review, we briefly discuss what is known about molecular mimicry followed by a discussion of the current understanding of dual TCRs. Finally, we discuss three mechanisms, including molecular mimicry, dual TCRs, and chimeric TCRs, by which dual reactivity of the T cell may play a role in autoimmune diseases.     

Biological Implications of HLA-DR Expression in Tumours

HLA-DR antigens show restricted tissue distribution in comparison with the more extensive expression of HLA class I molecules. This constitutive expression is genetically controlled by well-defined mechanisms. In addition, DR antigen expression can be induced by a variety of cytokines through different molecular genetic events that convert DR-negative epithelia into positive cells. In this review we analyse the two major pathological situations in which abnormal DR expression occurs: autoimmune diseases and tumour development. We hypothesize that conversion to DR-positivity may produce two opposite effects in both clinical situations: (1) a useful one in tumours associated with a good prognosis; and (2) a harmful one in autoimmune diseases with increased tissue damage.     

Impact of gut microbiota on gut-distal autoimmunity: a focus on T cells

The immune system is essential for maintaining a delicate balance between eliminating pathogens and maintaining tolerance to self-tissues to avoid autoimmunity. An enormous and complex community of gut microbiota provides essential health benefits to the host, particularly by regulating immune homeostasis. Many of the metabolites derived from commensals can impact host health by directly regulating the immune system. Many autoimmune diseases arise from an imbalance between pathogenic effector T cells and regulatory T (Treg) cells. Recent interest has emerged in understanding how cross-talk between gut microbiota and the host immune system promotes autoimmune development by controlling the differentiation and plasticity of T helper and Treg cells. At the molecular level, our recent study, along with others, demonstrates that asymptomatic colonization by commensal bacteria in the gut is capable of triggering autoimmune disease by molecular mimicking self-antigen and skewing the expression of dual T-cell receptors on T cells. Dysbiosis, an imbalance of the gut microbiota, is involved in autoimmune development in both mice and humans. Although it is well known that dysbiosis can impact diseases occurring within the gut, growing literature suggests that dysbiosis also causes the development of gut-distal/non-gut autoimmunity. In this review, we discuss recent advances in understanding the potential molecular mechanisms whereby gut microbiota induces autoimmunity, and the evidence that the gut microbiota triggers gut-distal autoimmune diseases.     

Infectious agents in the pathogenesis of primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a chronic progressive cholestatic liver disease which is characterized by the breakdown of self-tolerance to the highly conserved pyruvate dehydrogenase complex, specially the pyruvate dehydrogenase E2 complex (PDC-E2). The breakdown of the tolerance to such antigens leads to an autoimmune process characterized by portal inflammation and immune-mediated destruction of the intrahepatic bile ducts. Epidemiological studies have suggested that infections agents can trigger or even exacerbate the disease. Among other gram negative bacteria, Escherichia Coli, and Nosphingobium aromaticivorans are the most associated agents reported hitherto. Epidemiological and molecular evidence points towards molecular mimicry between some components of these microorganisms and specific amino-acid sequences that are present in proteins on normal cells of the biliary tract. In this review, we revisit all reports suggesting that infectious agents might be associated with the autoimmune pathogenesis of PBC. We also retrieve the immune molecular mimicry mechanisms that are likely involved with the autoimmune process in PBC.     

A monoclonal lewis rat myocyte line that responds to interferon-gamma: responsiveness with the potential to influence subsequent interactions with the immune system

In order to begin asking questions about immunopathology associated with the model of the neuromuscular disease experimental autoimmune myasthenia gravis, a monoclonal myocyte line, LE1, has been prepared from the Lewis rat. The LE1 myocyte clone was selected from among several clones produced based on its ease of maintenance in culture and for the stability of its phenotype, which is very similar to that reported for in vivo muscle and other cultured myocyte lines. Thus, LE1 cells were observed to produce, constitutively, the myocyte-associated neural cell adhesion molecule (CD56), the intracellular adhesion molecule (ICAM-1), and the acetylcholine receptor. LE1 cells were also observed to constitutively secrete relatively low levels of IL-6 and TGF-beta. Moreover, the LE1 cell line may be of use for predicting muscle responses to various immune mediators. For example, the inflammatory cytokine interferon-gamma (IFN-gamma) has been recently reported by others to play a role in experimental myasthenia gravis. Thus, it was of interest that LE1 cells could be activated by IFN-gamma to express increased levels of immunopathologically relevant membrane molecules such as ICAM-1 and Class II major histocompatibility molecules (i.e., RT-1B).     

Disease mimicry--a pathogenetic concept for T cell-mediated autoimmune disorders triggered by molecular mimicry?

Molecular mimicry is considered as a mechanism by which infectious pathogens may break immunological tolerance and cause autoimmune disease. It implicates that peptides shared between pathogen and host may induce cross-reactive immune reactions. According to this hypothesis, the resulting autoimmune response actually represents a secondary immune response. It is mediated by cross-reactive T cells that have been educated in a primary immune response against a particular pathogen. Using psoriasis vulgaris as a model, this article discusses the potential functional consequences molecular mimicry should have for the resulting autoimmune disease. It proposes that due to the functional memory of T cells, which is an integral feature of adaptive immunity, the phenotype of an autoimmune disease induced by molecular mimicry should reflect the immune mechanisms raised in the primary immune response. This process might be called 'disease mimicry'.     

Pathogenesis of autoimmune hepatitis: from break of tolerance to immune-mediated hepatocyte apoptosis

Understanding the pathogenesis and progression of autoimmune hepatitis (AIH) at the molecular level could prove essential in developing new preventive and therapeutic strategies. Recently developed murine models have enabled the identification of various mechanisms involved in the development and perpetuation of this autoimmune disorder. Studies on these models have shown that a peripheral break of tolerance against liver-expressed antigens is sufficient to induce an autoimmune liver disease, which can occur without prior liver damage. Recent data have also shown that the liver selectively recruits and induces the apoptosis of activated CD8+ T cells after an immune response. This process of T-cell trapping involves the expression of specific chemokines and adhesion molecules, and these molecules are believed to play an important role in the initiation and perpetuation of autoimmune hepatitis. Hepatocyte apoptosis, induced by autoreactive T cells, follows specific pathways that could be targeted by new therapeutic agents. Basic research on the break of immune tolerance against liver antigens would be beneficial for patients with autoimmune hepatitis, as well as those suffering from other chronic inflammatory liver diseases, such as primary biliary cirrhosis and graft-versus-host diseases.     

Monoclonal autoantibodies: an approach to studying autoimmune disease

Hybridoma technology has paved the way for new insights into mechanisms of autoimmunity and autoimmune disease. Autoantibodies and autoantigens can now be studied at the level of the individual molecule. The specificity of the autoimmune reaction, as well as its pathogenetic role in disease, may be more accurately assessed. Monoclonal autoantibodies which bind to red blood cells, IgG, DNA, RNA and ribonucleoprotein complexes have been prepared by several groups of investigators. The initial molecular and functional characterization of these immunoglobulins and their corresponding antigens is described.     

Molecular mimicry as an inducing trigger for CNS autoimmune demyelinating disease

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that affects about 0.1% of the worldwide population. This deleterious disease is marked by infiltration of myelin-specific T cells that attack the protective myelin sheath that surrounds CNS nerve axons. Upon demyelination, saltatory nerve conduction is disrupted, and patients experience neurologic deficiencies. The exact cause for MS remains unknown, although most evidence supports the hypothesis that both genetic and environmental factors contribute to disease development. Epidemiologic evidence supports a role for environmental pathogens, such as viruses, as potentially key contributors to MS induction. Pathogens can induce autoimmunity via several well-studied mechanisms with the most postulated being molecular mimicry. Molecular mimicry occurs when T cells specific for peptide epitopes derived from pathogens cross-react with self-epitopes, leading to autoimmune tissue destruction. In this review, we discuss an in vivo virus-induced mouse model of MS developed in our laboratory, which has contributed greatly to our understanding of the mechanisms underlying molecular mimicry-induced CNS autoimmunity.