Evidence for Fas-dependent and Fas-independent mechanisms in the pathogenesis of experimental autoimmune encephalomyelitis

To determine whether Fas or Fas ligand (FasL) plays a role in susceptibility to experimental autoimmune encephalomyelitis (EAE), we bred a TCR transgenic mouse specific for the Ac1-11 peptide of myelin basic protein to mice with inactivating mutations in Fas (lpr) or FasL (gld). Disease induction by peptide immunization in such mice produced similar disease scores, demonstrating that Fas/FasL interactions were not necessary to generate EAE. However, adoptive transfer experiments showed evidence that these interactions can play a role in the pathogenesis of EAE, shown most dramatically by the absence of disease following transfer of cells from a normal myelin basic protein TCR transgenic mouse into a Fas-deficient lpr recipient. Furthermore, transfer of cells lacking FasL (gld) into normal or gld recipients gave a diminished disease score. Thus, Fas/FasL interactions can play a role in the pathogenesis of EAE, but they are not required for disease to occur.     

Difference in pathogenesis between vitiligo vulgaris and halo nevi associated with vitiligo is supported by an HLA association study

Human leukocyte antigen (HLA) class II associations with two subtypes of vitiligo: vitiligo vulgaris and halo nevi associated with vitiligo were investigated. In previous studies associations between vitiligo and HLA antigens have been reported but these two subtypes have never been taken into account. However from a clinical and histological point of view, a difference in (auto)-immune pathogenesis can be expected. This difference might be reflected in an association with different HLA alleles. Seventy-six unrelated Dutch Caucasians, 40 with vitiligo vulgaris and 36 with halo nevi associated with vitiligo were included. A panel of randomly chosen HLA typed healthy Dutch blood donors (n = 2400) served as control population. HLA-DR and -DQ typing was carried out on blood samples by amplifying genomic DNA using polymerase chain reaction followed by dot blot hybridization with sequence specific oligonucleotides. The main outcome measures were odds ratio (OR), uncorrected P-value (P(u)) and corrected P-value. There were distinct differences in the clinical manifestations between vitiligo vulgaris and halo nevi associated with vitiligo with respect to precipitating factors, extent and progress of the disease and the association with other auto-immune diseases in the two subtypes and their respective first degree family members. Our stratification reveals differences in HLA class II between both subtypes and between subtypes and controls. A case-control association study showed a significant positive association of HLA-DR4 (OR = 2.787, P(u) = 0.0022) and DR53 (OR = 2.249, P(u) = 0.0153) and a negative association of HLA-DR3 (OR = 0.195, P(u) = 0.0024) with vitiligo vulgaris. The group with halo nevi associated with vitiligo did not show these associations, but had a significant negative association with HLA-DR11 (OR = 0.083, P(u) = 0.0067). In conclusion, the differences in HLA association within clinical subtypes of vitiligo support our suggestion that vitiligo vulgaris and halo nevi associated with vitiligo have distinct pathogenic mechanisms.     

Multistep pathogenesis of autoimmune disease

In the immune system, many tolerance checkpoints exist to prevent self-antigens from stimulating the relentless growth of self-reactive B and T lymphocytes. The genes and molecular pathways underpinning these checkpoints overlap with those involved in tumor suppression. As with an inherited predisposition to cancer, inherited defects in self-tolerance genes typically precipitate autoimmune disease stochastically after a latent phase. Multiple mutations, inherited and somatic, may be needed before a self-reactive clone bypasses sequential tolerance checkpoints resulting in the emergence of autoimmune disease.     

Evidence for an infarctive pathogenesis of acute and chronic gastroduodenal ulceration.

It is clear that all mucosal defensive mechanisms acting against aggressive ulcerogenic factors depend on adequate blood flow. When defence is active, ulcers tend to heal and do so faster when luminal aggression is prevented by reduction of acidity or eradication of H. pylori. Such successful treatment is so profitable that pharmaceutical companies invest vast fortunes on research into every aspect of therapy. This may explain why research on basic aetiology has been slower. Nevertheless there have been recent advances which increasingly point towards an ischaemic pathogenesis of both acute and chronic ulcers. We have been studying those ischaemic mechanisms that may be triggered by alteration of normal physiological processes, and we now have a body of evidence supporting an infarction-like mechanism induced by abnormal motility which might explain the initiation of both acute and chronic human ulceration. In this article we review the evidence for this and show that such a pathogenesis is compatible with the features and current concepts of gastro-duodenal ulceration. Perhaps the most striking feature of chronic ulcers is their singularity, and localisation to the lesser curvature and first part of the duodenum. Within the lesser curvature there is an increasing incidence from the oesophageal end towards pylorus, with maximal incidence in the incisural area (1). Duodenal ulcers occur on the anterior or posterior walls of the first 4 cm. uncommonly on the superior "cap" and rarely on the inferior wall. Such localisation points to a primary cause which, by analogy with other localised necroses eg coronary or stroke, is usually an infarction of an end-artery system.     

The genetics of generalized vitiligo and associated autoimmune diseases

Vitiligo is an acquired disorder in which patches of depigmented skin and often overlying hair, and mucous membranes, are the result of progressive autoimmune loss of melanocytes from the involved areas. Considered the most common pigmentary disorder, vitiligo involves complex interaction of environmental and genetic factors that ultimately contribute to melanocyte destruction, resulting in the characteristic depigmented lesions. In the past few years, studies of the genetic epidemiology of vitiligo have led to the recognition that generalized vitiligo is part of a broader autoimmune disease diathesis. Attempts to identify genes involved in susceptibility to generalized vitiligo have involved gene expression studies, genetic association studies of candidate genes, and genome-wide linkage analyses to discover new genes. These studies have begun to yield results that shed light on the mechanisms of vitiligo pathogenesis. It is anticipated that the discovery of biological pathways of vitiligo pathogenesis will provide novel targets for future approaches to the treatment and prevention of vitiligo and its associated autoimmune diseases.     

Significant role for Fas in the pathogenesis of autoimmune diabetes

Programmed cell death represents an important pathogenic mechanism in various autoimmune diseases. Type I diabetes mellitus (IDDM) is a T cell-dependent autoimmune disease resulting in selective destruction of the beta cells of the islets of Langerhans. beta cell apoptosis has been associated with IDDM onset in both animal models and newly diagnosed diabetic patients. Several apoptotic pathways have been implicated in beta cell destruction, including Fas, perforin, and TNF-alpha. Evidence for Fas-mediated lysis of beta cells in the pathogenesis of IDDM in nonobese diabetic (NOD) mice includes: 1) Fas-deficient NOD mice bearing the lpr mutation (NOD-lpr/lpr) fail to develop IDDM; 2) transgenic expression of Fas ligand (FasL) on beta cells in NOD mice may result in accelerated IDDM; and 3) irradiated NOD-lpr/lpr mice are resistant to adoptive transfer of diabetes by cells from NOD mice. However, the interpretation of these results is complicated by the abnormal immune phenotype of NOD-lpr/lpr mice. Here we present novel evidence for the role of Fas/FasL interactions in the progression of NOD diabetes using two newly derived mouse strains. We show that NOD mice heterozygous for the FasL mutation gld, which have reduced functional FasL expression on T cells but no lymphadenopathy, fail to develop IDDM. Further, we show that NOD-lpr/lpr mice bearing the scid mutation (NOD-lpr/lpr-scid/scid), which eliminates the enhanced FasL-mediated lytic activity induced by Fas deficiency, still have delayed onset and reduced incidence of IDDM after adoptive transfer of diabetogenic NOD spleen cells. These results provide evidence that Fas/FasL-mediated programmed cell death plays a significant role in the pathogenesis of autoimmune diabetes.     

Neutrophil ferroptotic death promotes autoimmune pathogenesis

Science China Life Sciences -     

Inhibition of experimental autoimmune vitiligo by oral administration of mushroom tyrosinase

Experimental autoimmune vitiligo was induced by intradermal injection of mushroom tyrosinase emulsified in complete Freund's adjuvant in female C57BL/6 mice. The onset of vitiligo was characterized by hair hypopigmentation and total melanocyte depletion in the basal layer of the epidermis. Oral administration of mushroom tyrosinase prevented the expression of mushroom tyrosinase induced experimental autoimmune vitiligo. Based on the results it is likely that oral administration of mushroom tyrosinase may have practical implications in vitiligo.     

Cathepsin S is required for murine autoimmune myasthenia gravis pathogenesis

Because presentation of acetylcholine receptor (AChR) peptides to T cells is critical to the development of myasthenia gravis, we examined the role of cathepsin S (Cat S) in experimental autoimmune myasthenia gravis (EAMG) induced by AChR immunization. Compared with wild type, Cat S null mice were markedly resistant to the development of EAMG, and showed reduced T and B cell responses to AChR. Cat S null mice immunized with immunodominant AChR peptides showed weak responses, indicating failed peptide presentation accounted for autoimmune resistance. A Cat S inhibitor suppressed in vitro IFN-gamma production by lymph node cells from AChR-immunized, DR3-bearing transgenic mice. Because Cat S null mice are not severely immunocompromised, Cat S inhibitors could be tested for their therapeutic potential in EAMG.     

Herpesvirus connection in the expression of autoimmune vitiligo in Smyth line chickens

The Smyth line (SL) chicken is an animal model for human vitiligo, a common acquired depigmentary disorder affecting about 1-2% of people worldwide. The vitiligo-like depigmentation in SL chickens typically develops when the birds are between 6 and 14 weeks of age and may affect 70-95% of hatch mates. The development of SL vitiligo is considered to depend on two interacting components, namely an inherent melanocyte defect and an autoimmune reaction to melanocytes. Recently, a role for an environmental factor in the expression of vitiligo was suggested by the observation that only 10% of SL chicks imported from the University of Massachusetts (UM) and reared in isolation at biosecurity level 2 (BSL 2) at the University of Arkansas (UA) exhibited vitiligo. Following further assessment of environmental differences between UA and UM SL chickens, three environmental factors that may have influenced the expression of SL vitiligo were identified. Included were housing condition, status of Mycoplasma synoviae infection, and turkey herpesvirus (HVT) vaccination status. Studies were subsequently conducted at UA and UM to assess the role of these environmental factors in the expression of SL vitiligo. M. synoviae infection was not found necessary for vitiligo expression in SL chickens. However, HVT emerged as a strong candidate for an important environmental factor in SL vitiligo. The connection between HVT and SL vitiligo was confirmed for both BSL 2 and conventional housing. Therefore, the observations reported here suggest a strong causative link between HVT infection and SL vitiligo.     

Maintenance of immune hyporesponsiveness to melanosomal proteins by DHICA-mediated antioxidation: Possible implications for autoimmune vitiligo

Melanocyte destruction in the skin of vitiligo patients has been considered to be a consequence of an autoimmune response against melanosomal proteins. However, little is known about the molecular mechanisms by which the immune system recognizes these sequestered intracellular self-proteins, which are confined in specialized organelles termed melanosomes, and is provoked into an autoimmune response to melanocytes. Here, we utilize a sucrose density-gradient ultracentrifugation protocol to enrich melanosomal components from dopachrome tautomerase (Dct)-mutant or wild-type melanocytes exposed to a pulse of hydrogen peroxide at a noncytotoxic concentration to evaluate their immunogenicity in mice challenged with the corresponding melanosomal proteins. The results demonstrate that enhanced humoral and cellular immune responses to a challenge with late-stage melanosomal proteins, especially with those derived from Dct-mutant melanocytes, are found in the immunized mice. To elucidate whether a reduced 5,6-dihydroxyindole-2-carboxylic acid (DHICA) content in melanin might cause a loss in antioxidative protection to the proteins, we incubated these melanosomal proteins in vitro with synthetic 5,6-dihydroindole (DHI)-melanin or DHI/DHICA (1:1)-melanin and then used them to immunize mice. T cell proliferation and IgG antibody responsiveness to the challenges were significantly induced by melanosomal proteins treated with DHI-melanin, but not by those treated with DHI/DHICA (1:1)-melanin. Moreover, we observed that melanosomal proteins derived from Dct-mutant melanocytes are subject to oxidative modifications that alter their antigenic configurations to attain an enhanced immunogenicity compared with those derived from wild-type melanocytes. From these results, we conclude that DHICA-mediated antioxidation plays a critical role in the maintenance of immune hyporesponsiveness to melanosomal proteins.     

Epidemiology of vitiligo and associated autoimmune diseases in Caucasian probands and their families

Generalized vitiligo is an autoimmune disorder characterized by acquired white patches of skin and overlying hair, the result of loss of melanocytes from involved areas. The most common disorder of pigmentation, vitiligo occurs with a frequency of 0.1-2.0% in various populations. Family clustering of cases is not uncommon, in a non-Mendelian pattern suggestive of multifactorial, polygenic inheritance. We surveyed 2624 vitiligo probands from North America and the UK regarding clinical characteristics, familial involvement, and association with other autoimmune disorders, the largest such survey ever performed. More than 83% of probands were Caucasians, and the frequency of vitiligo appeared approximately equal in males and females. The frequency of vitiligo in probands' siblings was 6.1%, about 18 times the population frequency, suggesting a major genetic component in disease pathogenesis. Nevertheless, the concordance of vitiligo in monozygotic twins was only 23%, indicating that a non-genetic component also plays an important role. Probands with earlier disease onset tended to have more relatives affected with vitiligo, suggesting a greater genetic component in early onset families. The frequencies of six autoimmune disorders were significantly elevated in vitiligo probands and their first-degree relatives: vitiligo itself, autoimmune thyroid disease (particularly hypothyroidism), pernicious anaemia, Addison's disease, systemic lupus erythematosus, and probably inflammatory bowel disease. These associations indicate that vitiligo shares common genetic aetiologic links with these other autoimmune disorders. These results suggest that genomic analysis of families with generalized vitiligo and this specific constellation of associated autoimmune disorders will be important to identify the mechanisms of genetic susceptibility to autoimmunity.     

New insights into the pathogenesis of cutaneous autoimmune disorders

T helper 17 (Th17) cells are characterized by the secretion of IL-17, a proinflammatory cytokine. They represent a newly described T helper subpopulation that is distinct from Th1 and Th2 lineages. Because of their pleiotropic activity on fibroblasts, keratinocytes, endothelial cells, neutrophils and memory T cells, Th17 cells are thought to be crucial in mediating tissue inflammation and autoimmunity. Autoimmune diseases were classically considered as Th1-mediated disorders such as rheumatoid arthritis or mixed Th1/Th2 diseases such as inflammatory bowel diseases, systemic lupus erythematosus, bullous diseases, but new evidence suggests the deep involvement of Th17 cells in their pathogenesis that, potentially, may address a selective therapeutic approach targeting the IL23/Th17 pathway. This review summarizes the current knowledge of the pathogenic contribution of Th17 cells in select cutaneous autoimmune disorders, including lupus erythematosus, scleroderma, dermatomyositis, bullous pemphigoid and pemphigus vulgaris.     

Evidence that Cd101 is an autoimmune diabetes gene in nonobese diabetic mice

We have previously proposed that sequence variation of the CD101 gene between NOD and C57BL/6 mice accounts for the protection from type 1 diabetes (T1D) provided by the insulin-dependent diabetes susceptibility region 10 (Idd10), a <1 Mb region on mouse chromosome 3. In this study, we provide further support for the hypothesis that Cd101 is Idd10 using haplotype and expression analyses of novel Idd10 congenic strains coupled to the development of a CD101 knockout mouse. Susceptibility to T1D was correlated with genotype-dependent CD101 expression on multiple cell subsets, including Foxp3(+) regulatory CD4(+) T cells, CD11c(+) dendritic cells, and Gr1(+) myeloid cells. The correlation of CD101 expression on immune cells from four independent Idd10 haplotypes with the development of T1D supports the identity of Cd101 as Idd10. Because CD101 has been associated with regulatory T and Ag presentation cell functions, our results provide a further link between immune regulation and susceptibility to T1D.     

Autoantigens as substrates for apoptotic proteases: implications for the pathogenesis of systemic autoimmune disease

Systemic autoimmune diseases are a genetically complex, heterogeneous group of diseases in which the immune system targets a diverse, but highly specific group of intracellular autoantigens. The clustering and marked concentration of these molecules in the surface blebs of apoptotic cells, and their modification by apoptosis-specific proteolytic cleavage and/or phosphorylation at these sites, has focused attention on a unique apoptotic setting as the potential initiating stimulus for systemic autoimmunity. This apoptotic event is likely to (i) occur in a microenvironment containing high concentrations of the targeted antigens, (ii) be pro-immune in nature (e.g. viral infection), and (iii) allow suprathreshold concentrations of antigen with non-tolerized structure (either novel fragments, post-translational modifications, or complexes) to enter the class II processing pathway and initiate a primary immune response. Defective clearance or reduced anti-inflammatory consequences of apoptotic material may be important susceptibility factors in this group of diseases. Once the primary immune response to apoptotic antigens has been initiated, other apoptotic events (occurring in the course of homeostasis or damage) may stimulate the secondary immune response with less stringency, resulting in flares.     

Early disease onset and increased risk of other autoimmune diseases in familial generalized vitiligo

Generalized vitiligo is an autoimmune disorder in which acquired white patches of skin and overlying hair result from autoimmune loss of melanocytes from involved areas. Although usually sporadic, family clustering of vitiligo may occur, in a non-Mendelian pattern typical of multifactorial, polygenic inheritance. Sporadic vitiligo is associated with autoimmune thyroid disease, pernicious anemia, Addison's disease, and lupus; these same disorders occur at increased frequency in patients' first-degree relatives. Here, we studied 133 'multiplex' generalized vitiligo families, with multiple affected family members. The age of onset of vitiligo is earlier in these 'multiplex' families than in patients with sporadic vitiligo. Affected members of the multiplex vitiligo families have elevated frequencies of autoimmune thyroid disease, rheumatoid arthritis, psoriasis, adult-onset insulin-dependent diabetes mellitus, pernicious anemia, and Addison's disease. Probands' unaffected siblings have elevated frequencies of most of these same autoimmune diseases, particularly if the proband had non-vitiligo autoimmune disease. Familial generalized vitiligo is thus characterized by earlier disease onset and a broader repertoire of associated autoimmune diseases than sporadic vitiligo. This mostly likely reflects a greater inherited genetic component of autoimmune susceptibility in these families. These findings have important implications for autoimmune disease surveillance in families in which multiple members are affected with vitiligo.     

CTLA4 polymorphisms are associated with vitiligo, in patients with concomitant autoimmune diseases

The cytotoxic T lymphocyte antigen4 (CTLA4) gene plays a critical role in the control of T cell activation. The gene encodes a surface molecule with inhibitory effects on activated T cells. Several studies have disclosed an association between the previously known variants of the CTLA4 gene and autoimmune disorders, but no study has as yet found any definite association between vitiligo and the CTLA4 polymorphisms. A recent study identified new candidate susceptibility polymorphisms in this region, associated with differential gene splicing and thereby the relative abundance of soluble CTLA4. To assess these new polymorphisms in patients with vitiligo, we genotyped 100 vitiligo patients and 140 healthy controls from the UK, for these novel polymorphisms. No association was found in patients with isolated vitiligo, but a significant association was seen in patients with vitiligo and other autoimmune diseases. The results indicate that the polymorphisms in the CTLA4 gene region confer susceptibility to vitiligo when occurring together with other autoimmune diseases, but not in patients with isolated vitiligo. This raises the possibility that there are two distinct forms of vitiligo where only a subgroup of patients may have a disease caused by the autoimmune destruction of melanocytes.     

热休克蛋白与自身免疫病相关研究进展

热休克蛋白(heat shock proteins,HSPs)是动物体内一类热应激蛋白,是机体受到高热或其他理化生物等因素刺激时产生的特殊蛋白质。HSPs与自身免疫病的发生发展有着密切关系,在正常生理状态下,HSPs可以在天然免疫反应和适应性免疫反应中分别发挥作用,以帮助机体应对过激环境;而在异常病理条件下,HSPs可参与多种自身免疫病的发生发展。重点概述了HSP22、HSP27、HSP60、HSP70、HSP90与几种常见自身免疫病的相关作用。