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Histocompatibility (HL-A) Antigens Associated with Psoriasis
Abstract
HL-A phenotypes were determined in 44 unrelated and 22 related psoriatic patients to establish frequency of HL-A. HL-A13 was present in 12 of 44 unrelated patients, and in three of 89 controls (a difference significant at p less than 0.0001). W17 (Te57) was also present in 10 of 44 unrelated patients and in 17 family members with psoriasis examined of a dominant pedigree with psoriasis over four generations. Two members of the family not having W17, siblings 42 and 46 years old, did not have psoriasis. These findings suggest that HL-A phenotypes may be of value in studies regarding the etiology of psoriasis.
... Nonsynonymous HLA-C variation detected in rs1130838 has been associated with psoriasis and Behcet's disease (Lee et al., 2012). Psoriasis is a common multifactorial chronic skin disease with a genetic background that was prompted investigations in the early 1970s into associations with the HLA complex on chromosome 6p (Russell et al., 1972). The global psoriasis prevalence rate is approximately 2-3% among the world's population (Sewerin et al., 2019), reaching 8-11% in some Northern European countries (Egeberg et al., 2019) and ~ 4% in Lithuania. ...
... Different HLA class I and II alleles and haplotypes have been reported to be associated with psoriasis; however, the association tends to vary between patients of different racial and ethnic backgrounds. The association of HLA class I and II antigens were first reported by serologic methods in 1970s [7]. In the following years, it was reported by many independent groups, including our own and another group from Pakistan showing that the HLA-Cw*06:02 allele is the major and most consistently demonstrated risk factor [8][9][10][11][12][13][14][15]. Association of HLA-Cw*06:02 was greater in early onset psoriatic patients and the disease was more severe in HLA-Cw*06:02 positive patients [16]. ...
Introduction:
The human leukocyte antigen (HLA) region on chromosome 6p21 is well known to carry the most important genetic factors in susceptibility to psoriasis. Different HLA alleles and haplotypes have been reported to be associated with psoriasis in different populations. Psoriasis has a variable age of onset and, based on this, it can be classified into two types; type I with age of onset before 40 years of age and type II with age of onset after 40 years of age. The objective of this study was to determine the association of HLA class I and class II alleles and haplotypes with disease and stratification using age of onset in Pakistani psoriatic patients.
Methods:
A group of 603 individuals (326 cases and 277 controls) were analyzed for HLA class I and II alleles and haplotype association by sequence specific PCR. The association was further analyzed according to the age of onset of the patients.
Results:
We found that HLA alleles B*57 and Cw*06:02, DQB1*03:03:02 are strongly associated with early onset psoriasis, while alleles B*15, DRB1*13:02 and DQB1*03:03:02 are associated with late-onset psoriasis. Cw*06:02 allele was not associated with late-onset psoriasis patients. Allele DQB1*03:03:02 had the highest odds ratio in all patients. We found a novel association specifically with late-onset psoriasis samples with the haplotype HLA-A*11; B*15; Cw*04; DRB1*15; DQB1*05 (Pc = 3.60 × 10-7). We also found strong association with previously reported extended haplotype EH-57.1: HLA-B*57; Cw*06:02; DRB1*07:01; DQB1*03:03:02 in all our patients (Pc = 8.34 × 10-07).
Conclusion:
Our results show that different HLA class I and II alleles and haplotypes are associated with psoriasis at different age of onset. In this study, we have reported novel alleles and haplotype association with late-onset psoriasis. Our data confirm the previous strong associations with HLA alleles and haplotypes and also reports novel alleles and haplotype association in Pakistani psoriasis patients.
... Many epidemiological studies point to the role of both inherited and environmental factors in psoriasis [7,8]. In 1972, a potential role of the HLA region on chromosome 6 in association with the psoriasis phenotype was first documented [9,10]. Later, multiple loci on chromosomes 1,2,4,5,8,16,17, and 20 predisposed to psoriasis were suggested in several investigations [11][12][13]. ...
Background:
Psoriasis is a chronic inflammatory autoimmune disease that is considered linked to genetic and environmental factors such as stress. Since the neurotransmitter dopamine has a close association with stress configuration, it can be a candidate for relieving psoriasis representation. In addition to the CNS, immune cells can play a decisive role in regulating immune functions through dopamine synthesis and the expression of its receptors. Altered response of immune cells to dopamine as well as distorted expression of dopamine receptors (DRs) in immune cells have been reported in some chronic inflammatory conditions.
Objective:
This study aims the evaluation of dopamine receptor (DR1-DR5) gene expression in mononuclear blood cells of psoriatic patients in comparison with normal individuals.
Method:
We isolated peripheral mononuclear cells (PBMCs) from blood samples followed by total RNA extraction, cDNA synthesis, and real-time PCR using specific primer pairs.
Result:
We found that all types of DRs are expressed in the PBMCs of normal and psoriatic individuals. We also concluded that compared to controls, DR2 and DR4 were overexpressed in psoriasis patients while DR3 was low-expressed.
Conclusion:
Increased expression of DR2 and DR4 along with decreased expression of DR3 in PBMCs of psoriasis patients not only provide new insight into the pathogenesis of psoriasis but may also be effective in designing future therapeutic strategies attributable to psoriasis.
... [2][3][4] The association of HLA molecules with the occurrence of psoriasis vulgaris and psoriatic arthritis is widely described in the literature. [5][6][7][8][9][10][11][12][13][14][15] Studies in populations of different ethnic origins show the increased frequency of different HLA specificities and haplotypes in patients with psoriasis when compared to control groups. 8,[16][17][18] Often, this frequency is even higher in patients with early-onset psoriasis and familial history of the disease. ...
Background:
The study of HLA classes I and II in Brazilian psoriasis patients may contribute to a better understanding of their association with the disease.
Objective:
To describe HLA classes I and II of Brazilian patients with psoriasis, with or without arthritis, compare them to controls and correlate HLA markers with epidemiological and evolutional aspects of psoriasis.
Methods:
A total of 55 patients with more than 5 years of psoriasis, with or without arthritis, answered a questionnaire on ethnic background and disease severity. A total of 134 bone marrow donors were controls. HLA class I and II genotyping was determined by PCR-SSP.
Results:
Mean age was 42.4 years; 23 women and 32 men. HLA-B*57 was present in 23.6% patients and in 7.5% controls (p=0.00200, OR= 3.8381), and HLA-C*06 in 29.1% patients and in 16.4% controls (p= 0.04832, OR=2.0886). HLA-B*57 and HLA-C*18 were significantly present in patients with arthritis (p=0.00104, OR=6.6769 and p=0.00269, OR=16.50, respectively). HLA-B*57 was significantly present in patients with history of erythroderma (p=0.00548, OR= 5.1059), as was HLA-C*06 (p=0.02158, OR=3.0545). HLA-B*57 was also frequent in patients with history of hospital internment due to psoriasis (p= 0.00094, OR=7.8909) and in the ones with history of systemic treatment for psoriasis (p= 0.00011, OR= 5.3733). Haplotype HLA-A*02 B*57 C*06 DRB1*07DQB1*03 was the most common among the patients (p= 0.00069, OR= 3.528).
Conclusion:
HLA-B*57 and HLA-C*06 were significantly increased in the patients indicating risk for psoriasis. HLA-B*57 remained high in patients with history of erythroderma, hospital internment, systemic treatment, and psoriatic arthritis, showing association with disease severity. HLA-C*18 was significantly high only in patients with psoriatic arthritis. HLA-B*57 and HLA-C*06 and haplotype HLA-A*02B*57Cw*06DRB1*07 DQB1*03 seen in this study were already described before, associated with psoriasis. HLA-Cw*18 was not described in other populations in association with psoriasis.
... Recently, psoriasis has been considered to be a kind of genetic-, autoimmune-, and metabolic-derived disease. It has been speculated that when a genetically predisposed individual is exposed to specific environmental factors (EFs) that act along with epigenetic alternations, he/she may present psoriatic skin alterations (48,49). Well-known EFs that are strongly linked to psoriasis include dietary habits along with obesity, microbiota, infections, alcohol intake, tobacco smoking, and psychological factors (50,51). ...
It is an indisputable fact that obesity is associated with a series of health problems. One important hallmark of obesity is excessive accumulation of lipids in the adipocyte, especially triglyceride (TG). Currently, the adipocyte has been considered not only as a huge repository of excess energy in the form of fat but also as an important source of multiple hormones and cytokines called adipokines. In obesity, the adipocyte is dysfunctional with excessive production and secretion of pro-inflammatory adipokines, such as tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and leptin. On the other hand, accumulating evidence has shown that leptin plays a vital role in stimulating angiogenesis, controlling lipid metabolism, and modulating the production of pro-inflammatory cytokines. Furthermore, the various activities of leptin are related to the wide distribution of leptin receptors. Notably, it has been reported that enhanced leptin levels and dysfunction of the leptin signaling pathway can influence diverse skin diseases. Recently, several studies revealed the roles of leptin in wound healing, the hair cycle, and the pathogenic development of skin diseases, such as psoriasis, lupus erythematosus, and dermatological cancers. However, the exact mechanisms of leptin in modulating the dermatological diseases are still under investigation. Therefore, in the present review, we summarized the regulatory roles of leptin in the pathological progression of diverse diseases of skin and skin appendages. Furthermore, we also provided evidence to elucidate the complicated relationship between leptin and different dermatological diseases, such as systemic lupus erythematosus (SLE), psoriasis, hidradenitis suppurativa, and some skin tumors.
... LOP patients are also more likely to be anxious compared with EOP patients 3 . The major histocompatibility complex (MHC) region, also known as human leukocyte antigen (HLA) was first associated with psoriasis in 1972 4 . HLA-C*06:02 in the class I HLA region has been proven to be the most significant risk allele for psoriasis in both European 5 and Chinese populations [6][7][8] . ...
Background:
Psoriasis vulgaris is a chronic inflammatory skin disease which occur at any age. It can be clinically classified into two age-onset subtypes: early-onset psoriasis (EOP; <40 years) and late-onset psoriasis (LOP; ≥40 years). More evidence showed EOP and LOP have different genetic architecture, notably the risk allele human leukocyte antigen (HLA)-C*06:02 located within the major histocompatibility complex (MHC) region, which was reported to be the outstanding variant associated with EOP. However, genetic structure of EOP and LOP have not been fully elucidated.
Objective:
To investigated HLA genetic heterogeneity between EOP and LOP in China.
Methods:
We first calculated the MHC-based heritability of EOP and LOP respectively. Then, we conducted a large-scale, stratified analysis including 7,097 EOP, 1,337 LOP patients, and 9,906 healthy controls by using MHC target sequencing data from a previous study.
Results:
We observed that HLA alleles collectively explained a larger heritability of EOP (27.4%) than LOP (11.3%). Further association analysis identified three independent loci (HLA-C*01:02, p=6.70×10-8; HLA-A amino acid position 9, p=3.27×10-17; and HLA-A amino acid position 161, p=5.75×10-10) that confer specific susceptibility to EOP. Our data also confirmed HLA-C*06:02 as an independent psoriasis-associated variant, contributing a higher degree of risk to EOP than LOP. Moreover, case-case analysis confirmed that HLA-C*06:02-positive psoriasis patients have earlier onset.
Conclusion:
Our analysis indicating that different genetic background underlie the EOP and LOP. We believe these findings will serve to predict psoriasis risk in the future and facilitate clinical decision.
... Psoriasis is considered to be a kind of genetic-, autoimmune-, and metabolic-derived disease. It has been speculated that when the genetically predisposed individual is exposed to specific environmental factors (EFs) that act along with epigenetic alternations, he may develop psoriatic skin changes [35][36][37][38][39][40][41]. The well-known EFs that are strongly linked to psoriasis include dietary habits along with obesity, microbiota, infections, alcohol intake, tobacco smoking, and psychological factors [42][43][44]. ...
Leptin is an adipokine, adipocyte-derived compound, which acts both as a hormone and cytokine. It is mainly synthesized by adipocytes of white adipose tissue. Leptin possesses pleiotropic functions including, among others, stimulation of angiogenesis and production of proinflammatory cytokines. The various types of leptin activity are related to the wide distribution of leptin receptors. This adipokine acts by activating intracellular signaling cascades such as JAKs (Janus kinases), STATs (signal transducers and activators of transcription), and others.
In a course of obesity, an increased serum level of leptin coexists with tissue receptor resistance. It has been reported that enhanced leptin levels, leptin receptor impairment, and dysfunction of leptin signaling can influence skin and hair. The previous studies revealed the role of leptin in wound healing, hair cycle, and pathogenesis of skin diseases like psoriasis, lupus erythematosus, and skin cancers. However, the exact mechanism of leptin’s impact on the skin is still under investigation. Herein, we present the current knowledge concerning the role of leptin in psoriasis and selected skin diseases.
... Falchuk and co workers (Falchuk et al, 1972) discovered that the frequency of the HLA-B8 allele was significantly higher in patients with celiac disease than in a control sample of healthy individuals. Russell and co-workers (Russell et al, 1972) as well as White and co workers (White et al, 1972) observed a similar association between HLA-B 13, B17 alleles and psoriasis. In subsequent years, a number of other diseases have been reported to occur more frequently in individuals with certain HLA alleles than in individuals who have other alleles. ...
A unique feature of the human Major Histocompatibility Complex genes is their extensive polymorphism which is localised mainly within those regions encoding the groove of the HLA molecules. Comparison of HLA allelic sequences reveals a patchwork pattern in which an individual allele comprises a unique combination of sequence motifs, each of which is shared with other alleles, and only a few alleles have a unique sequence that is not present elsewhere in the HLA region. This feature of the HLA polymorphism has complicated the application of DNA-based methods that rely on sequence identification to type the HLA genes. To overcome this problem, two novel high resolution HLA typing methods were developed. The first utilises a set of only 40 probes, which identify the recombinational motifs present in exon 2 and 3 of the HLA class I genes, allowing a unique hybridisation pattern for each allele. The unambiguous identification of the alleles is achieved by the use of a new allelic separation technique called Complementary Strand Analysis. The second method, Reference Strand mediated Conformation Analysis (RSCA), differs from conventional sequence based typing methodologies in that the HLA type is assigned on the basis of accurate measurement of conformation dependent DNA mobility in polyacrylamide gel electrophoresis. RSCA utilises a fluorescent labelled locus specific reference DNA to selectively modify the molecular conformation of the tested DNA. The use of laser based instrumentation and computer software, in addition to internal DNA markers for correction of gel variability, allows the discrimination of HLA alleles which differ by one nucleotide in a DNA fragment nearly as large as a kilobase in length. RSCA has been successfully applied in blind studies of HLA typing demonstrating that is reproducible, able to identify new alleles, and to resolve ambiguous heterozygous combinations.
... The history of genetic research on psoriasis dates back to the early 1970s, when Russell et al. and White et al. independently observed that tissue class I compatibility antigens B37 and B57 encoded by the major histocompatibility complex (MHC) genes located on the sixth chromosome (6p21.33) may be genetic markers of psoriasis susceptibility [2,3]. The results of the research conducted in subsequent years among ethnically and racially different populations showed that this relationship is secondary to correlation with the HLA-Cw6 antigen and is associated with the phenomenon of non-random allele coupling in haplotypes characteristic of the MHC region -linkage disequilibrium (i.e., co-inheritance). ...
Psoriasis is a multifactorial disease in which genetic, environmental and epigenetic factors regulating gene expression play a key role. In the "genomic era", genome-wide association studies together with target genotyping platforms performed in different ethnic populations have found more than 50 genetic susceptible markers associated with the risk of psoriasis which have been identified so far. Up till now, the strongest association with the risk of the disease has been proved for HLA-C*06 gene. The majority of other psoriasis risk SNPs are situated near the genes encoding molecules involved in adaptive and innate immunity, and skin barrier function. Many contemporary studies indicate that the epigenetic changes: histone modification, promoter methylations, long non-coding and micro-RNA hyperexpression are considered as factors contributing to psoriasis pathogenesis as they regulate abnormal keratinocyte differentiation and proliferation, aberrant keratinocytes - inflammatory cells communication, neoangiogenesis and chronic inflammation. The circulating miRNAs detected in the blood may become specific markers in the diagnosis, prognosis and response to the treatment of the disease. The inhibition of expression in selected miRNAs may be a new promising therapy option for patients with psoriasis.
... It is possible that the T cells primed with these M protein peptides can recognize the atypical K16 and K17 keratin epitopes via molecular mimicry and lead to autoimmunity [100]. Also, genetic association studies showing the same risk alleles for psoriasis and streptococcal tonsillitis support the hypothesis of molecular mimicry-mediated autoimmunity triggered by streptococcal infections [101][102][103][104]. Additional examples of consequences of mimicry between human tissues and M proteins include rheumatic fever and poststreptococcal glomerulonephritis. ...
Streptococci are a broad group of Gram‐positive bacteria. This genus includes various human pathogens causing significant morbidity and mortality. Two of the most important human pathogens are Streptococcus pneumoniae (pneumococcus) and Streptococcus pyogenes (group A streptococcus or GAS). Streptococcal pathogens have evolved to express virulence factors that enable them to evade complement‐mediated attack. These include factor H binding M (S. pyogenes) and pneumococcal surface protein C (PspC) (S. pneumoniae) proteins. In addition, S. pyogenes and S. pneumoniae express cytolysins (streptolysin and pneumolysin), which are able to destroy host cells. Sometimes the interplay between streptococci, the complement and antistreptococcal immunity may lead to an excessive inflammatory response or autoimmune disease. Understanding the fundamental role of the complement system in microbial clearance and the bacterial escape mechanisms is of paramount importance for understanding microbial virulence, in general, and, the conversion of commensals to pathogens, more specifically. Such insights may help to identify novel antibiotic and vaccine targets in bacterial pathogens to counter their growing resistance to commonly used antibiotics.
... The complexity of the underlying pathology of both diseases makes it difficult to pinpoint a single cause and it is generally accepted that (Bazso et al., 2014). Disturbances in the frequency of HLA antigens in psoriatic patients was shown in 1972, suggesting that HLA phenotypes were important and could have relevance to the susceptibility of an individual to the disease (Russell et al., 1972;White et al., 1972). A strong association with the major histocompatibility complex (MHC) class I region, known as PSORS1 (psoriasis susceptibility locus 1) was shown by Tiilikainen et al., 1980. ...
Dyslipidaemia is known to be one of the major contributory factors in atherosclerosis and cardiovascular disorders. In particular, increased circulating low-density lipoprotein (LDL) and accumulation in the vascular bed is thought to have damaging effects. Abnormal lipid profiles in patients with psoriasis have also been identified and it is hypothesised that a similar pathogenesis underlies the two conditions. In particular, the oxidative modification of the LDL particle (oxLDL) is thought to promote inflammation. This thesis therefore aims to investigate whether lipid accumulation and oxidation influences inflammation and vascular function.
The inflammatory events occurring in psoriasis were modelled in this thesis using in vitro assays for angiogenesis, endothelial cell migration, inflammatory cell recruitment under flow and immune cell proliferation. Human umbilical vein endothelial cells (HUVECs) were used as a model endothelium to study the effects of oxidised lipids on vascular function. In order to analyse the lipid contribution to inflammation, serum was depleted of lipids and compared to serum with a full lipid profile. The addition of lipids such as ox-/LDL was evaluated in complete and delipidated serum.
This investigation showed that in the absence of serum lipids, endothelial tube formation was significantly impaired, in addition to endothelial cell migration being inhibited. The proliferation of peripheral blood mononuclear cells (PBMCs) was also abrogated in the absence of serum lipids. Serum lipid depletion did not, however, have any effect on the ability of TNFα- or IFNg-stimulated endothelial cells to recruit leukocytes under shear stress. The addition of oxLDL had biphasic effects on endothelial responses by significantly enhancing migration at lower concentrations of 5µg/mL, yet significantly inhibiting this response at higher concentrations of 100µg/mL. In the recruitment assay, higher concentrations of oxLDL were able to increase the basal recruitment of neutrophils to the endothelial monolayer whereas lower concentrations had no effect on recruitment. Native LDL had no significant effect on these parameters at equivalent concentrations. OxLDL-induced endothelial migration was inhibited by the addition of a sphingosine kinase inhibitor and a blockade of S1P1 on endothelial cells. OxLDL induced migration was not affected by the inhibition of PAF-R. Flow cytometry was used to assess the expression of oxLDL receptors on HUVEC, showing no expression of LOX-1 but slight increases in CD36 expression, although not reaching statistical significance.
These data indicate that serum lipids are key in supporting in the angiogenic response, likely by affecting endothelial cell migration, in addition to having an important role in the maintenance of immune cell proliferation. Oxidised lipids have also been shown to have biphasic effects on inflammatory processes, dependent on concentration. These results also highlight the critical role for S1P in oxLDL-induced endothelial cell migration, with the blockade of sphingosine kinase and S1P1 effectively inhibiting these vascular responses. This thesis highlights the importance of the oxidation of LDL and subsequent oxLDL concentration on regulating inflammation. Further understanding in the mechanisms of oxLDL-induced inflammation may provide a therapeutic target in psoriasis and other related inflammatory conditions.<br/
... Genes and epigenetics. The genetic predisposition to psoriasis was established many years ago [8], and to-date 424 genes loci with single nucleotide polymorphism have been proven to be associated with psoriasis [9]. However, many studies have shown that these are not the sole critical factors in the pathogenesis of the disease: the role of epigenetic modifications has been emphasized along with environmental factors and lifestyle habits [2,10]. ...
Introduction and objective:
Psoriasis isa quite common, chronic and immune-mediated skin disorder. The prevalence of psoriasis differs in various countries, but it is said to affect 2% of the world's population in general. Psoriasis has many different clinical features but all lesions have the same characteristic: erythema, thickening and scale, although other clinical features are also connected, such as psoriatic arthritis, obesity and metabolic syndrome. All of these may lead to conditions impairing the quality of life. This review is an attempt to summarize recent data regarding environmental factors, together with epigenetic markers and processes playing an important role in psoriasis.
State of knowledge:
Many different environmental factors play a role in genetically predisposed patients. This is causes epigenetic alternations which may be a linking part in the whole process. Many studies have indicated a connection between psoriasis and various genes and antigens. The presence of HLA-Cw6 is common as well a strong link between its presence and the onset of psoriasis being observed. The main alternations are DNA methylation, histone's modifications and the role of microRNA. Excessive reaction is usually not present without a triggering factor. Environmental factors are mostly rated, such as drugs, life style and habits (smoking, alcohol), diet, physical trauma (skin injury provoking Koebner phenomenon), stress, microorganism and infections.
Conclusions:
The correlation between pathogenesis of psoriasis and environmental risk factors, together with epigenetic alternations still require more investigation. Education about diet habits, nutrition, weight loss and healthy lifestyle seems to be important during the treatment of psoriasis.
... Already in early medical literature, familial forms of psoriasis were described (Squire, 1873). Antigen testing of lymphocytes could uncover that the HLA type was associated with psoriasis in a polygenic manner, except for patients where psoriasis outbreak was induced by streptococcus (Russell et al., 1972). PSORS1 locus was later identified, containing HLA-C but also ten other genes, and sequencing could be performed thanks to technological developments. ...
Long-lived tissue-resident memory T cells (TRM) reside in nonlymphoid organs and can drive direct cytotoxicity, focal cytokine release and potent tissue-wide anti-infectious responses upon antigenic challenge. TRM cells poised to pathogenic responses have been identified in active and resolved psoriasis and mice models of allergic contact dermatitis (ACD). It is challenging to investigate the interactions between TRM cells and the local microenvironment in human tissues, and whether these cells promote disease in the absence of circulating T cells is less studied. This thesis focuses on the functional consequences of TRM cell activation inside the skin.
PAPER I: TRM cells can provide protection from infections. The retention marker CD49a was correlated to both the epidermal location of skin TRM cells and their cytotoxicity. IL-15 unleashed the killing capacities of CD8+CD103+CD49a+ T cells. The expression of CD49a in CD8+CD103+ skin T cells was associated with more IFN-γ release compared to CD8+CD103+CD49a-, which were conversely better IL-17 producers. CD49a expression delineated a CD8+ TRM cell specialization that was conserved in two inflammatory skin diseases psoriasis and vitiligo that were respectively enriched for CD8+CD103+CD49a- and CD8+CD103+CD49a+ TRM cells.
PAPER II: Psoriasis is linked to overproduction of IL-17 and Type 1 interferon is implicated as a disease trigger in the early events transforming never-lesional psoriasis (NLP) into full-blown psoriasis. CCR6+CD49a- TRM cells poised towards IL-17 production were enriched in NLP, possibly due to microbe-induced epidermal chemotaxis. Activation of skin-resident T cells in NLP skin triggered Type 1 interferon tissue responses, potentially via IFN-γ-induced release of IFN-α in keratinocytes. As IFN-γ-potent TRM cells accumulate in NLP epidermis, our findings suggest that Type 1 interferon release in NLP could be driven by TRM cells.
PAPER III: TRM cells poised to IL-17 and IL-22 production are retained in the epidermis in resolved psoriasis. In healthy and diseased skin, the activation of T cells within skin explants using the pan-T cell-activating antibody OKT-3 led to interferon-driven core-response CXCL10 and CXCL9 expression. Additionally, IL-17-specific transcriptional signature was induced in resolved and active psoriasis sample, and the magnitude of this response was correlated with relapse shortly upon withdrawal of UVB treatment.
PAPER IV: An upregulation of S100As transcripts persisted in the long-term in the epidermis of patients with resolved allergic contact dermatitis (ACD), indicating a disease scar. While inflammatory transcripts CXCL10, GZMB, and MMP12 were normalized after antigen exclusion for two months and two years, they were quickly induced in resolved epidermis upon exposure to the allergen. MMP12 was specifically upregulated in the epidermal compartment and codes for a protein capable of degrading the collagen IV that is a constituent of the skin basement membrane.
In conclusion, the TRM-driven tissue responses in human healthy and inflamed skin are highly compartmentalized and disease-specific. This concords with the functional heterogeneity of TRM cells themselves but also relies on their interplay with the stromal cells, which can help unveil pathogenic mechanisms in these relapsing-remitting inflammatory skin diseases. Preventing the TRM cell establishment or favoring their displacing by topical treatments could lead to significant improvements in the care of patients suffering from inflammatory diseases.
... Among all the MHC loci, the best characterized is undoubtedly the classic human leukocyte antigen (HLA). It has long been established that the HLA is associated with psoriasis [11]. The MHC is recognized as a major susceptibility locus for psoriasis; indeed, class I molecules on antigen-presenting cells are involved in activating T cells that are crucial in psoriasis pathophysiology [12]. ...
Background: Psoriasis is a common, chronic inflammatory skin disorder, which can significantly impact quality of life. Despite major breakthroughs in our understanding of the pathogenesis of psoriasis, the chronological order of the underlying mechanisms leading to the development of psoriatic plaques remains to be completely understood. Summary: Although psoriasis is classically perceived as a T-cell disease, it is now well recognized that T lymphocytes do not function in exclusivity. This theory is supported by evidence from transgenic murine models that develop marked psoriasiform disease. In addition, immune cells and cytokines regulate both early and late events involved in the pathogenesis of psoriasis. Key Messages: Psoriasis is a complex disease – a dynamic interplay between immune cells, keratinocytes, and various other skin-resident cells, such as endothelial and immune cells. The contribution of each cell type is crucial in the initiation and maintenance phases of psoriatic alterations.
... The role of MHC in psoriasis etiology has been the subject of much speculation, and the first genetic investigation on this topic was reported more than 40 years ago (Russell et al., 1972). Even though dozens of susceptibility loci have been identified, a large fraction of disease heritability can be explained by the variations within MHC region, suggesting its critical importance for the disease. ...
Major histocompatibility complex (MHC), also known as human leukocyte antigen (HLA) in humans, is one of the most genetically diverse regions in the genome of various species. The human MHC contains about 400 genes in a ∼7.6-Mb span located on the short arm of the chromosomal region 6p21.3. According to the NHGRI-EBI Catalog of published genome-wide association studies (http://www.ebi.ac.uk/gwas/) in HLA region, more than 500 associations have been identified for about 200 traits or phenotypes, including primary immune deficiencies, autoimmune diseases, susceptibility to infections, malignancies, and psychiatric conditions (Welter et al., 2014). For example, multiple sclerosis is associated with HLA-DRB1∗1501 (Handunnetthi et al., 2010); the control of HIV viral load is associated with variants near HLA-C (Kulpa and Collins, 2011). Some acute drug reactions are associated with specific HLA alleles. Carbamazepine-induced Stevens–Johnson syndrome and toxic epidermal necrolysis have been strongly associated with HLA-B*1502 in Han Chinese population and HLA-A*3101 in European populations (Chung et al., 2004; McCormack et al., 2011). The HLA-B*13:01 is associated with the development of the dapsone hypersensitivity syndrome among patients with leprosy (Zhang et al., 2013).
... In severe psoriasis cases, patients benefit from early antimicrobial treatment of streptococcal throat infections or tonsillectomy, suggesting a causal link (12)(13)(14). The major histocompatibility complex (MHC) region contains a risk allele(s) for psoriasis, with HLA-C*06:02 being the most widely replicated association (15)(16)(17). The prevalence of a pharyngeal GAS culture positivity has been shown to be higher among the HLA-C*06: 02-positive than the HLA-C*06:02-negative psoriasis patients (18). ...
Pharyngeal tonsillitis is one of the most common upper respiratory tract infections and Group A streptococcus is the most important bacterial pathogen causing it. While most patients experience tonsillitis only rarely, a subset of patients suffer from recurrent or chronic tonsillitis or pharyngitis. The predisposing factors for recurring or chronic form of this disease are not yet fully understood but genetic predisposition has been suggested. A genetic association study using Illumina's Immunochip SNP array was performed to search for new genetic biomarkers in pharyngeal tonsillitis. Over 100,000 SNPs relevant to immune-mediated diseases were analyzed in a cohort of 95 patients subjected to tonsillectomy due to recurrent/chronic tonsillitis and 504 controls. Genetic association between the cases and controls showed strongest association with two peaks in the HLA locus (OR 3.7-4.7, p=4.9-5.7x10 ⁻⁶ ). Further analysis with imputed classical HLA alleles suggested the known psoriasis risk allele HLA-C*06:02 as a risk factor for tonsillitis (p=4.8 x 10 ⁻⁴ , OR 2.3). In addition, the imputed HLA haplotype HLA-C*06:02/HLA-B*5701 , a reported risk haplotype in psoriasis, had the strongest risk for tonsillitis, too (p=8.0 x 10 ⁻³ , OR 5.5). These findings further support the previously reported link between streptococcal throat infections and psoriasis.
... Tiilikainen et al. [67] found that the prevalence of HLA-Cw6 was 45.9% in patients with psoriasis vulgaris and 7.4% in controls. A higher prevalence of human leukocyte antigen (HLA)-B13-positive cases among patients with psoriasis was observed compared to control phenotypes [68]. However, among diverse HLA alleles, specific HLA alleles alone are not adequate for the development of psoriasis, which could imply that other genes are involved in psoriasis pathogenesis [69]. ...
Psoriasis is a complex chronic inflammatory cutaneous disorder. To date, robust molecular mechanisms of psoriasis have been reported. Among diverse aberrant immunopathogenetic mechanisms, the current model emphasizes the role of Th1 and the IL-23/Th17 axis, skin-resident immune cells and major signal transduction pathways involved in psoriasis. The multiple genetic risk loci for psoriasis have been rapidly revealed with the advent of a novel technology. Moreover, identifying epigenetic modifications could bridge the gap between genetic and environmental risk factors in psoriasis. This review will provide a better understanding of the pathogenesis of psoriasis by unraveling the complicated interplay among immunological abnormalities, genetic risk foci, epigenetic modification and environmental factors of psoriasis. With advances in molecular biology, diverse new targets are under investigation to manage psoriasis. The recent advances in treatment modalities for psoriasis based on targeted molecules are also discussed.
... All these data showed why psoriasis was accepted as a heritable disease but not 100% as a genetic disease. Psoriasis was first associated with the major histocompatibility complex (MHC) region in the short arm of the 6th chromosome in 1972 [20][21][22]. MHC is an intense region of the genome and contains HLA-I and HLA-class human leukocyte antigens. In fact, the 80-200 kb long region in the HLA-C gene region has been accepted as the Psoriasis susceptibility gene region (PSOR1) [23]. ...
... Previous studies on multiply affected families have found several susceptibility loci for Ps [47]. The most strongly associated locus is on chromosome 6p21 within the MHC region (PSORS1) [48]. Family-based association studies have confirmed that HLA-C is directly involved in psoriatic susceptibility [49,50]. ...
Objectives:
To confirm the association of previously discovered psoriasis (Ps) risk loci with the disease in a Polish population and to create predictive models based on the combination of these single nucleotide polymorphisms (SNPs).
Material and methods:
Thirty-eight SNPs were genotyped in 480 Ps patients and 490 controls. Alleles distributions were compared between patients and controls, as well as between different Ps sub-phenotypes. The genetic risk score (GRS) was calculated to assess the cumulative risk conferred by multiple loci.
Results:
We confirmed associations of several loci with Ps: HLA-C, REL, IL12B, TRIM39/RPP21, POU5F1, MICA. The analysis of ROC curves showed that GRS combining 16 SNPs at least nominally (uncorrected P<0.05) associated with Ps (GRS-N) had significantly better discriminative power than GRS combining SNPs associated with Ps after the Bonferroni correction (AUC 0.776 vs. 0.750, P = 1 x 10-4) or HLA-C (AUC 0.776 vs. 0.694, P<1 x 10-5). On the other hand, adding additional SNPs to the model did not improve its discriminatory ability (AUC 0.782 for GRS combining all SNPs, P>0.05). In order to assess the total risk conferred by GRS-N, we calculated ORs according to GRS-N quartile - the Ps OR for top vs. bottom GRS-N quartiles was 12.29 (P<1 x 10-6). The analysis of different Ps sub-phenotypes showed an association of GRS-N with age of onset and family history of Ps.
Conclusions:
We confirmed the association of Ps with several previously identified genetic risk factors in a Polish population. We found that a GRS combining 16 SNPs at least nominally associated with Ps had a significantly better discriminatory ability than HLA-C or GRS combining SNPs associated with Ps after the Bonferroni correction. In contrast, adding additional SNPs to GRS did not increase significantly the discriminative power.
... tok psoriasisban Az elsô genetika vizsgálatok az 1970-es években kezdôdtek. Ekkor már szerológiai módszerek segítségével felfigyeltek a humán leukocyta antigénekre (HLA) vagy másnéven fô hisztokompatibilitási génekre (14), melyek az immunrendszer mûködésében töltenek be központi szerepet (15). ...
... The major genetic determinant however remains within the MHC region. MHC is the home of genes encoding human leukocyte antigens (HLA) and HLA associations in psoriasis have been recognized for over 35 years (Russell et al., 1972). ...
... Genome-wide association studies have identified many psoriasis-associated genetic loci in the Caucasian population (Nair et al., 1997;Russell et al., 1972;Tiilikainen et al., 1980;Tsoi et al., 2012). However, most genome-wide association study signals lie within noncoding regions of the human genome (Maurano et al., 2012). ...
Psoriasis is a chronic inflammatory skin condition resulting from a complex interplay among the immune system, keratinocytes, susceptibility genes, and environmental factors. However, the pathogenesis of psoriasis is not completely elucidated. microRNAs represent a promising class of small, noncoding RNA molecules that function to regulate gene expression. Although microRNA research in psoriasis and dermatology is still relatively new, evidence is rapidly accumulating for the role of microRNAs in the pathogenesis of psoriasis and other chronic inflammatory conditions. In this article, we present a comprehensive review of what is known about microRNAs and their role in the pathogenesis of psoriasis.
No definite association has been shown between Crohn's disease or ulcerative colitis and the distribution of HLA antigens. No association either occurs with the enteropathic arthritis complicating these diseases. HLA-B27 has been found in a high proportion of patients with spondylitis complicating inflammatory bowel disease, although not as high as in ‘idiopathic’ ankylosing spondylitis. It seems, however, that the possession of B27 in a patient with inflammatory bowel disease confers a greater risk of the development of ankylosing spondylitis than in subjects without bowel disease.
In obesity, adipocytes are dysfunctional with excessive production and secretion of pro-inflammatory hormones and cytokines, ie, adipokines, such as tumor necrosis factor α (TNF-α), interleukin 6 (IL-6) and leptin. Accumulating evidence has shown that leptin possesses pleiotropic functions including stimulation of angiogenesis and production of pro-inflammatory cytokines. Furthermore, various leptin associated activities involve a wide distribution of leptin receptors. For example, increased serum leptin was associated with tissue receptor resistance in metabolic syndrome. Although increased serum leptin, receptor and signaling impairment are involved in wound healing, hair cycle and the pathogenesis of many skin diseases such as psoriasis and lupus erythematosus as well as skin cancer, its exact role remains unclear. In the present article, we discuss the biochemistry of leptin action and its potential role in the pathophysiology of diverse skin diseases.
Linked Article: Talamonti et al. Br J Dermatol 2017; 177:489–496.
The association of psoriasis with HLA-B13 and -B17 in American Caucasian populations was first reported by Russell et al.1 and White et al.2 in 1972. Since then, several investigators have observed these associations in Caucasian patients from the United States, Canada, and various European and Asian countries (Table 7.1). However, the association with B13 is not consistent in all of the studies. This discrepancy cannot be attributed to the differences between the populations or the sample size. Other studies on the same populations with smaller sample size reported a significant increase in the frequency of B13. This type of discrepancy was probably the result of serologic and/or technical problems associated with typing some of the HLA specificities. Data on the frequency of B17 in various Caucasian groups are more consistent; all of the studies reported a significant increase in frequency. The combined estimate of relative risk for all the Caucasian Groups is 5.30 (Table 7.1).
It is now well established that the intensity of graft rejection is conditioned by the degree of antigenic difference between the donor and the recipient. The phenomenon of rejection is the result of an immune response of the host, directed against transplantation or histocompatibility antigens present on the donor cells. Histocompatibility testing represents the identification by serological techniques or other methods of the transplantation antigens. Many studies conducted in inbred mice have led to the recognition of at least 30 histocompatibility systems. One of them, the H-2 system, is considered to be the major histocompatibility system, because incompatibility with respect to H-2 antigens will result in rapid rejection of grafts. Transplants performed between strains of mice differing only in antigens belonging to the minor system will survive for a longer time. Now similar major systems have been identified in other animals: the AgB system in the rat, the B system in the chicken, the DL-A system in the dog, the H-I system in the rabbit, the ChL-A system in the chimpanzee. So far, two major antigenic systems have been observed to be histocompatibility barriers in man: the ABO system and the HL-A system. In this review, we will discuss the HL-A system only and concentrate on the serology, the genetics, and the clinical applications, especially for transplantation, of this recently discovered immunogenetic system.
Two cases were presented of generalized pustular psoriasis. The first case, who was 40-year-old man, had more typical psoriasis proceeding the acute pustular flare. Systemic administration of corticosteroids brought the skin lesions under control.
The second case was 44-year-old man, who developed generalized pustular psoriasis without a prior history of psoriasis. Systemic administration of corticosteroids, methotrexate and hydroxyurea was ineffective and ultimately he died. We supported Bakers' opinion that in generalized pustular psoriasis two quite distinct sub-groups were discernible.
The study of the major histocompatibility complex in man, which is called the HLA system, has emerged during the last 15 years as a new biomedical research field. It covers a broad spectrum of topics ranging from basic studies of regulatory mechanisms controlling immune responsiveness to clinical investigations of genetic aspects of a variety of human diseases.
Since the discoveries in 1972 by Russell et al. (1972) and Falchuk and Strober (1972) that psoriasis and coeliac disease are strongly associated with certain HLA antigens, it has become clear that the HLA system is involved in the etiology or pathogenesis, or both, of a variety of diseases. These relationships between HLA and disease are of considerable clinical and theoretical importance because they provide new ways for the study of etiology, genetics, and nosology of HLA-related diseases, and in a few cases they may have diagnostic and prognostic implications. One of the most fascinating aspects of this research involves attempts to establish the mechanisms by which HLA confers susceptibility or resistance to disease. Such mechanisms have been dealt with in detail abundantly elsewhere (Dausset and Svejgaard, 1977; McDevitt and Bodmer, 1972; Svejgaard et al., 1977). However, at this time, there have been very few definite explanations established for the HLA-disease associations. Accordingly, in this survey, we shall focus solely on a somewhat more neglected field: the contribution of HLA studies to our knowledge of the genetics of diseases. First, we shall give a general concept of genetic disorders and discuss how studies of genetic markers may help determine the mode of inheritance of disease susceptibility and resistance. Next, we shall summarize the present knowledge about HLA and disease associations and finally describe examples that illustrate how this knowledge may guide our interpretation of disease-inheritance patterns.
Psoriatic arthritis (PsA) has been defined as an inflammatory arthritis, usually seronegative for rheumatoid factor, associated with psoriasis [1]. Other clinical features associated with PsA include the presence of spondylitis and sacroiliitis, dactylitis (swelling of the whole digit), enthesitis (inflammation at tendon insertion), and extra-articular manifestations of seronegative spondyloarthropathies such as iritis, urethritis, inflammatory bowel changes, and aortic root dilatation. The original description of PsA was that of a mild disease compared with rheumatoid arthritis (RA) [2]. Moll and Wright described five clinical patterns of PsA:
predominantly distal joint disease, with distal interphalangeal (DIP) joint involvement;
an oligoarthritis, usually asymmetric;
a symmetric polyarthritis indistinguishable from RA;
arthritis mutilans; and
spondyloarthritis.
Etwa 1,5% der Bevölkerung westlicher Industrienationen erkranken während ihres Lebens an einer chronischen, entzündlichen Hauterkrankung, die durch das Auftreten von erythematösen, stark schuppenden Plaques und teilweise auch durch Arthritiden gekennzeichnet ist: Psoriasis vulgaris. Aufgrund ihrer Häufigkeit und ihres besonderen Erscheinungsbildes, des oft lebenslang rezidivierenden Krankheitsverlaufes sowie des hohen persönlichen Leidensdruckes der Patienten gehört Psoriasis zu den wichtigsten, aber auch rätselhaftesten Erkrankungen in der Dermatologie. Die Entschlüsselung ihrer Pathogenese ist nach wie vor eine der großen Herausforderungen in der Dermatologie. Prof. Dr. med. Dr. h.c. mult. Otto Braun-Falco hat sich während seiner langen Schaffensperiode auch dieser Aufgabe mit großem Engagement gestellt und durch seine Arbeiten das Wissen über das Wesen der Psoriasis und ihrer Entstehung entscheidend vorangetrieben.
Given that many skin disorders have an immunologic basis or involve inflammatory reactions, compounds affecting the afferent or the effector limbs of immune responses play a central role in dermatologic therapy. Topical glu-cocorticosteroids (GCs) represent the mainstay of anti-inflammatory and im-munosuppressive treatment of inflammatory skin diseases. However, despite their broad and common usage, some mechanisms by which GCs exert their functions still remain obscure. It is thought that binding of a GC to a cyto-plasmic glucocorticosteroid receptor (GCR) [65] leads to dissociation of a complex composed of a GCR and two heat-shock proteins [51]. This dissociation is followed by migration of the GCR-GC complex into the nucleus and binding to specific DNA sites called glucocorticoid response elements (GC-REs). A number of genes have been identified that are regulated by GC-REs, including lipocortin-1, an inhibitor of phospholipase A2 [22]. In addition, there is evidence that GCs can directly inhibit phospholipase A2 [51]. Both direct and indirect effects on phospholipase A2 synergistically decrease mediators of inflammation such as thromboxanes, prostaglandins, and leuko-trienes, thus inhibiting leukocyte attraction to sites of inflammation [27, 28].
Klinische und experimentelle Evidenz belegen eine zentrale Rolle von T-Lymphozyten bei der Pathogenese der Psoriasis (Christophers 1996). Diese Ansicht wird gestützt durch die Assoziation von Psoriasis mit bestimmten MHC-Allelen, wie -B13, -B17, -Bw57, und -Cw6 (Mallon et al. 1997); (Russell et al. 1972); (Tiilikainen et al. 1980); (Watson et al. 1972); (White et al. 1972), den therapeutischen Effekt immunsuppressiver Substanzen wie Cyclosporin A (Ellis et al. 1986); (Mueller and Herrmann 1979) und das Lymphozytenspezifische Toxin DAB389IL-2 (Gottlieb et al. 1995), die Assoziation eines bei Psoriatikern gehäuft aktivierten Gens mit einem IL-2 regulierenden Gen (Tomfohrde et al. 1994), und das Abheilen psoriatischer Läsionen nach Knochenmark-Transplantationen (Eedy et al. 1990); (Jowitt u. Yin 1990).
Psoriasis is one of the most common skin diseases present throughout the worldwide population affecting about 2% of individuals [1]. It has several different clinical appearances, but the most common phenotype consists of symmetrically distributed, persistent erythematous scaling plaques.Within these cutaneous lesions, there is infiltration
of inflammatory cells, prominent keratinocyte hyperplasia with altered differentiation,
neovascularization of the dermis,and activation of immunocompetent cells-T cells and
dendritic antigen-presenting cells [2]. One of the most difficult problems for investigators studying this disease is to be able to determine with certainty which cellular and molecular events are of primary importance and which changes are secondary. The confederacy of cell types participating in this disorder, together with the panoply of cytokines and the rapidity of evolution and disappearance of skin lesions, has confounded even the most astute clinicians and bench researchers for the past century. Perhaps the greatest obstacle has been the lack of an appropriate and relevant animal model that recapitulates all of the important and characteristic cutaneous changes present in human psoriatic plaques.
Es muß hier nicht betont werden, daß Psoriasis vulgaris eine der bedeutendsten Hauterkrankungen ist, sie gehört zum Alltagsgeschäft der Dermatologie. Während die Diagnose einer Psoriasis zumindest in ihrer klassischen Ausprägung meist noch relativ einfach ist, kann bereits ihre Behandlung trotz der großen therapeutischen Fortschritte der letzten Jahre außerordentlich schwierig sein. Wirklich schwer ist es auch heute noch, die Psoriasispathogenese zu erklären. Dabei ist eigentlich keine dermatologische Erkrankung so intensiv beforscht worden und dabei dennoch so unerklärt geblieben wie eben die Psoriasis.
In Untersuchungen der vergangenen Jahre wurde überzeugend nachgewiesen, daß dem Haupthistokompatibilitätskomplex (MHC) eine zentrale Bedeutung für die genetische Kontrolle und Regulation der Immunantwort zukommt [10]. Hochinteressant war in diesem Zusammenhang deshalb die Entdeckung, daß die Strukturgene für 3 Komponenten des Komplementsystems, dieses wichtigen Mediatorsystems immunologischer Reaktionen, ebenfalls im MHC lokalisiert sind und daß sie zudem einen genetischen Polymorphismus aufweisen. Es handelt sich um die Komplementfaktoren C2, C4 und Bf [1, 5, 8].
Surveillance has been described as the systematic collection of data pertaining to the occurrence of specific diseases, the analysis and interpretation of these data, and the dissemination of consolidated and processed information to contributors to the program and other interested persons. (57) The principles have been well set forth by Langmuir(41) for the United States Center for Disease Control (CDC) and by Raška(57) for the World Health Organization (WHO), and were a major focus of discussion of the Twenty-first World Health Assembly in 1968.(70) The techniques of surveillance have become a part of national and international programs of disease control. This chapter will discuss the background and elements of traditional surveillance, the concept and uses of serological epidemiology, and their application to the control of infectious diseases.
Aseptic arthritis associated with genital-tract infection is probably the commonest form of acute arthritis affecting young adult males in the western world. In the light of recent highly significant advances in the fields of genetics and microbiology this condition is also of prime importance as the archetype of a genetically determined disorder, which is precipitated by external environmental influences. As awareness of this form of arthritis increases, so the considerable breadth of the spectrum of clinical features is becoming apparent, with, in particular, increasing recognition of patients with mild disease and an excellent prognosis. This disorder is also being diagnosed more frequently in women. In recent years, the definitions and terms used to apply to this form of arthritis have come under close scrutiny and it is clear that no existing term satisfactorily describes the whole spectrum of disease presently recognised as resulting from urogenital or gastrointestinal infection, without infection being present in the joint. Consequently, a plethora of terms has been introduced; an attempt at rationalisation of terminology is presented below. We consider that the term ‘reactive arthritis’ most accurately describes this multifaceted disorder.
1801 beschrieb R. Willan [26], daß Psoriasis familiär vorkommt und daher eine erbliche Komponente vorliegen sollte. Heute, nahezu 200 Jahre später, sind weder die genaue Art der Vererbung noch verantwortliche Gene bekannt. In einer grundlegenden Studie zeigte G. Lomholt 1963 [11], daß 91% der Patienten mit Psoriasis zumindest einen erkrankten Verwandten 1. oder 2. Grades aufweisen. Mehrere folgende Studien lieferten ähnliche Ergebnisse. Weitere Untersuchungen an ein- oder zweieiigen Zwillingen ergaben, daß die Konkordanzrate, daß beide Geschwister an Psoriasis erkranken, bei monozygoten Zwillingen (70 %) erheblich erhöht ist im Vergleich zu dizygoten Zwillingen (23%, [11]). Daraus läßt sich ableiten, daß genetische Faktoren für die Entstehung der Psoriasis von Bedeutung sind. Aus der nicht loo-prozentigen Konkordanzrate bei monozygoten Zwillingen folgert man, daß außerdem exogene Einflüsse bei der Auslösung oder beim Wiederauftreten dieser Hautkrankheit eine Rolle spielen.
During the last few decades, the treatment of inflammatory skin disorders consisted mainly of systemic and topical glucocorticosteroids, but their use is limited due to potential side effects. Immunomodulatory macrolides such as cyclosporin and tacrolimus have recently shown therapeutic efficacy in such disorders. However, side effects such as hypertension and nephrotoxicity may occur after oral administration. Thus, a topical formulation was needed for the treatment of inflammatory skin disorders.
Psoriatic arthritis (PsA) is a common disease arising from a complex interplay between genetic, environmental and immune related factors. PsA exhibits one of the largest known recurrence risks among fi rst degree relatives in a complex rheumatic disease. While there is substantive evidence supporting a strong genetic component of PsA, it has been diffi cult to elucidate genes specifi c to PsA pathogenesis. Investigating the genetic etiology of PsA is inherently challenging given the existence of gene-gene interactions, gene-environment interactions as well as a potential contribution of copy number variants (CNVs) and epigenetic factors. This chapter will provide an overview of the genetics basis of PsA focusing on candidate gene studies, genome-wide linkage and association-based studies, in addition to highlighting the genetics related to PsA pharmacotherapy (i.e., pharmacogenetics).
Psoriasis has long been considered a genetic disorder. The fi rst observation that psoriasis is an inherited, familial skin disorder was made in 1957. Extensive epidemiologic evidence and monozygotic twin concordance studies confi rmed familial clustering of this chronic infl ammatory disease and drove scientifi c investigation into the genetic basis of psoriasis. Since 1957, the list of psoriasis-associated genetic polymorphisms, including some rare causal mutations, has grown tremendously due to advanced high-throughput genotyping platforms and statistical methods. Nevertheless, the majority of psoriasis patients lack known psoriasis- associated susceptibility loci and the exact molecular mechanisms by which polymorphisms contribute to psoriasis remains poorly understood. Recent work points to a complex interplay between genetics, epigenetics, and the infl ammatory signaling networks of skin and immune cell mediators. In contrast, other mutations appear to be causative, such as the recently identifi ed mutations in IL36RN and CARD14, and shed light on new immunologic pathways driving pustular psoriasis. Evidence is also rapidly accumulating for the role of epigenetic changes in psoriasis heritability. The decreasing cost and rapid advancements in genetic technologies in combination with the formation of multi-institutional patient registries will likely result in a better understanding of the “missing heritability” in psoriasis and other complex, multigenic diseases.
The discoveries of a number of associations between various HLA factors and certain diseases have made it possible to obtain new important information on subdivisions of disease entities and on the genetic backgrounds of the diseases, and have thrown new light on their pathogeneses. The practical clinical value of these associations is still limited. However, HLA typing of fetal cells can help in the prenatal diagnosis of 21-hydroxylase deficiency when a couple earlier have given birth to an affected child, and it is possible to predict the affection status of siblings of probands with idiopathic haemochromatosis by HLA typing the family. Siblings who are HLA identical with the proband have the genetic background for the disease and should be followed closely so that depletion of the iron stores can be instituted before organ damage develops. Because of the strong association between HLA-B27 and ankylosing spondylitis and reactive arthritis (including Reiter's disease), HLA typing may help in the diagnosis of early, unclear cases with these disorders. Moreover, reactive arthritis seems to run a more severe course in B27-positive patients, and thus HLA typing can be of prognostic value and may help when deciding the intensity of the treatment. It seems likely that future studies will open new possibilities for a practical use of HLA typing in clinical medicine.
The diseases covered below all feature erythematous or papular lesions which often become covered with scale. The term papulosquamous is most often used in the USA but fails to correctly describe diseases such as pityriasis rosea which has erythematous macules and then scale, but never papules. Thus we prefer erythematosquamous, even though it is not widely used in English. Most of these diseases have an unclear etiology and their appearance in the same chapter should not be interpreted as evidence of any biologic relationship.
The genetics of psoriasis has been studied with a questionnaire requesting information on presence or absence of the disease in relatives of 698 probands and 104 controls (spouses of probands). A statistically significant familial concentration of the disease has been demonstrated which, together with twin studies, supports the concept that hereditary factors contribute to the etiology of psoriasis. Pedigree analysis and frequencies of psoriasis among siblings of probands were not consistent with inheritance of genetic differences at a single autosomal or x-linked locus, even with decreased penetrance due to delayed age of onset. These findings plus further analysis suggested that psoriasis is determined by multifactorial inheritance. Estimates of heritability of liability for psoriasis were consistent among parents (64%) and siblings (65%) of probands. Hereditary factors play an important role in the etiology of psoriasis.
Twenty-seven patients with Hodgkin's disease and over a hundred healthy unrelated individuals have been typed for eight HL-A antigens and their leucocyte phenotypes were determined. The frequency of the HL-A5 specificity was higher among the patients with Hodgkin's disease than control subjects, the difference being highly significant statistically. This finding, which supports previous work,1 suggests that there is a correlation between the HL-A phenotype and susceptibility to Hodgkin's disease.
The microdroplet lymphocyte cytotoxicity test was examined thoroughly in an effort to increase the reproducibility of the test. The discrepancy rate in a large series of tests was reduced from 5.16% at the start of this study to the present 0.95% by introducing certain modifications in the technique. Variables connected with the isolation of lymphocytes, handling of antisera, quality of antisera, amount of complement, incubation temperature, duration of incubation, fixing of reactions, and reading of reactions were studied. The method which has resulted appears to be reproducible, simple, and readily usable on a large scale.
A new class of genes that controls the formation of specific immune responses has been identified.
Allogeneic antiserums against human lymphocytes were specifically inhibited by M protein from beta hemolytic group A Streptococcus pyogenes, type 1. Analogous M proteins from streptococcus types 3, 4, 5, 6, 12, and 14 had little or no inhibitory activity. The specific inhibition by M protein is not a result of anticomplementary activity or of coating of the lymphocyte surface. Streptococcal polysaccharide and 73 other polysaccharides were inactive. Because all seven HL-A specificities tested were inhibited, it is inferred that M1 protein has a structure common to human histocompatibility antigens.
The genetics of psoriasis has been studied with a questionnaire requesting information on presence or absence of the disease in relatives of 698 probands and 104 controls (spouses of probands). A statistically significant familial concentration of the disease has been demonstrated which, together with twin studies, supports the concept that hereditary factors contribute to the etiology of psoriasis. Pedigree analysis and frequencies of psoriasis among siblings of probands were not consistent with inheritance of genetic differences at a single autosomal or x-linked locus, even with decreased penetrance due to delayed age of onset. These findings plus further analysis suggested that psoriasis is determined by multifactorial inheritance. Estimates of heritability of liability for psoriasis were consistent among parents (64%) and siblings (65%) of probands. Hereditary factors play an important role in the etiology of psoriasis.
Systemic lupus erythematosus is a disease characterized by several immunologic abnormalities. We determined the HL-A antigens of 40 patients by a standard lymphocyte cytotoxicity test. Specificity HL-A8 was present in 33 per cent, and W15 (LND) in 40 per cent of the patients, as compared to control population frequencies of 16 per cent (p less than 0.025) and 10 per cent (p less than 0.0005), respectively. Nineteen other HL-A antigens did not differ significantly between patients and the control population, and no unusually frequent phenotypes were observed. The association between histocompatibility loci and susceptibility to certain diseases may be mediated by histocompatibility-linked immune response genes analogous to such associations demonstrated in mice. Other possible mechanisms for this association are that histocompatibility antigens represent specific receptor sites for attachment of a virus and that "cross-tolerance" enables viral antigens to mimic certain histocompatibility antigens.
The HL-A2 leucocyte antigen was found to be present in a significantly higher percentage of 485 patients with chronic glomerulonephritis than in 428 normal control subjects. No correlation could be shown between any of the ABO groups and chronic glomerulonephritis. There was no statistically significant difference in the frequency of HL-A2 when the controls were compared with 280 patients with a variety of other diseases. The trend toward an excess of HL-A2 positives among patients with glomerulonephritis was also seen in a study of 108 sibships, though the difference fell short of statistical significance. It was concluded that an HL-A2 positive person was about 1.5 times as likely to develop chronic glomerulonephritis as an HL-A2 negative person.
ATTEMPTS to define leucocyte groups in man serologically have been hampered by the scarcity of immune human antisera and the capriciousness of the leuco-agglutination reaction1. The method recorded here for assaying lymphocyte cytotoxins in a microscale was developed to circumvent these difficulties. Its extreme sensitivity permits performance of 1,000 or more tests with 1 ml. of antiserum. Furthermore, lymphocytes obtained from one finger-prick sample of blood are sufficient for 100 separate tests. The basic innovation in handling these small quantities of serum and cells and in gaining a greater than ten-fold increase in sensitivity over present-day methods is the performance of the reaction in microdroplets submerged under oil. This permits reduction in numbers of target cells to as few as 500 cells in contrast to the 50,000 or so cells required for previously described cytotoxicity tests2-4. Since the sensitivity of cytotoxicity is inversely proportional to the number of cells used2,3, an increase of sensitivity in the range of 10-100 times may be expected. Unlike the usual de Fonbrune oil chamber employed in micromanipulation, use of a `dish' with a cover-glass bottom facilitated rapid addition of reagents and cells with a microsyringe.