Fourteen sequence variants that associate with multiple sclerosis discovered by meta-analysis informed by genetic correlations.

A meta-analysis of publicly available summary statistics on multiple sclerosis combined with three Nordic multiple sclerosis cohorts (21,079 cases, 371,198 controls) revealed seven sequence variants associating with multiple sclerosis, not reported previously. Using polygenic risk scores based on public summary statistics of variants outside the major histocompatibility complex region we quantified genetic overlap between common autoimmune diseases in Icelanders and identified disease clusters characterized by autoantibody presence/absence. As multiple sclerosis-polygenic risk scores captures the risk of primary biliary cirrhosis and vice versa (P = 1.6 × 10-7, 4.3 × 10-9) we used primary biliary cirrhosis as a proxy-phenotype for multiple sclerosis, the idea being that variants conferring risk of primary biliary cirrhosis have a prior probability of conferring risk of multiple sclerosis. We tested 255 variants forming the primary biliary cirrhosis-polygenic risk score and found seven multiple sclerosis-associating variants not correlated with any previously established multiple sclerosis variants. Most of the variants discovered are close to or within immune-related genes. One is a low-frequency missense variant in TYK2, another is a missense variant in MTHFR that reduces the function of the encoded enzyme affecting methionine metabolism, reported to be dysregulated in multiple sclerosis brain.

Patient-reported Outcomes and Clinical Response in Patients with Moderate-to-severe Plaque Psoriasis Treated with Tonsillectomy: A Randomized Controlled Trial.

Psoriasis is a chronic inflammatory skin disease with profound effects on patients' health-related quality of life (HRQoL). Twenty-nine patients with plaque psoriasis and a history of streptococcal-associated psoriasis exacerbations were randomly assigned to tonsillectomy (n = 15) or control (n = 14) groups and followed for 24 months. Patients were evaluated with the Psoriasis Disability Index, Psoriasis Life Stress Inventory and Psoriasis Area and Severity Index. HRQoL and psoriasis-related stress improved significantly in the tonsillectomy group compared with the control group (p = 0.037 and p = 0.002, respectively), with a mean 50% improvement in HRQoL and a mean 59% improvement in psoriasis-induced stress. Clinical improvement correlated significantly with improved HRQoL (r = 0.297, p = 0.008) and psoriasis-related stress (r = 0.310, p = 0.005). Of the tonsillectomized patients, 87% concluded that the procedure was worthwhile. Tonsillectomy may improve quality of life for selected patients with plaque psoriasis.

HLA-Cw6 homozygosity in plaque psoriasis is associated with streptococcal throat infections and pronounced improvement after tonsillectomy: A prospective case series.

BACKGROUND: Carriage of the HLA-Cw*0602 allele is associated with a particular set of clinical features and treatment responses in psoriasis. Tonsillectomy can improve psoriasis. OBJECTIVES: We sought to evaluate whether HLA-Cw*0602 predicts a favorable outcome after tonsillectomy of patients with psoriasis. METHODS: This prospective case series followed up 28 tonsillectomized patients with plaque psoriasis for 24 months. The Psoriasis Area and Severity Index, Psoriasis Disability Index, and Psoriasis Life Stress Inventory were used for assessment. Tonsils were swabbed for bacteria and patients genotyped for HLA-Cw*0602. RESULTS: After tonsillectomy, HLA-Cw*0602 homozygotes showed significantly more improvement, compared with heterozygous and HLA-Cw*0602-negative patients. Thus, Psoriasis Area and Severity Index score was reduced by 82% in the homozygous patients compared with 42% and 31%, respectively (P < .001), Psoriasis Disability Index score improved by 87% compared with 38% and 41%, respectively (P < .001), and Psoriasis Life Stress Inventory score was 82% reduced compared with 60% and 54%, respectively (P < .001). The homozygotes more often had psoriasis onset associated with a throat infection (P = .007) and an increased frequency of streptococcal throat infections per lifetime (P = .038). LIMITATIONS: Few patients were included and some data were retrospective. CONCLUSIONS: Homozygous HLA-Cw*0602 carriage in plaque psoriasis may predict a favorable outcome after tonsillectomy.

Throat Infections are Associated with Exacerbation in a Substantial Proportion of Patients with Chronic Plaque Psoriasis.

Streptococcal throat infections are known to trigger or exacerbate psoriasis, and several studies support the benefit of tonsillectomy. To evaluate the potential of tonsillectomy as a treatment, we used a retrospective study-specific questionnaire to assess the proportion of psoriasis patients with sore throat-associated psoriasis exacerbations. Our survey sampled 275 psoriasis patients. Of patients with plaque psoriasis, 42% reported sore throat-associated psoriasis exacerbations, and of patients with confirmed streptococcal infections, 72% reported aggravation. Notably, women and patients with early onset psoriasis were more likely to report psoriasis exacerbation after a sore throat (p < 0.001, p = 0.046, respectively). Other psoriasis aggravation factors were more common in patients with sore throat-associated exacerbations (p < 0.01). Of tonsillectomized patients, 49% reported subsequent improvement and had more frequent sore throat-associated aggravation of psoriasis than patients who did not improve after tonsillectomy (p = 0.015). These findings suggest a closer association between sore throats, streptococcal throat infections and plaque psoriasis than reported previously.

Defective immunoglobulin A (IgA) glycosylation and IgA deposits in patients with IgA nephropathy.

Defective glycosylation and immune complex (IC) formation may be of primary importance in immunoglobulin A nephropathy (IgAN) pathogenesis. The aim of this study was to determine whether defective IgA1 glycosylation might support renal deposition of IgA and disease activity. IgA was isolated from the serum of 44 IgAN patients and 46 controls and glycosylation analysed by ELISA using glycan-specific lectins. IgA was measured by immunodiffusion and immune complexes by ELISA. IgA subclasses in IC deposits in kidney glomeruli were identified by immunohistochemical methods. A significant increase in N-acetylgalactosamine (GalNAc) in terminal position (p = 0.02) observed in some of the IgAN patients, became more pronounced when sialic acid was removed from IgA1, indicating enhanced expression of α-2,6-sialyltransferase in patients compared with controls (p < 0.0001). Patients with defective galactosylation had lower serum IgA than other IgAN patients (p = 0.003). IgAN patients with both IgA1 and IgA2 glomerular deposits (21.7%) had increased GalNAc in terminal position (p = 0.003). Taken together, our results show that increased IgA glycosylation in IgAN associates with low levels of IgA, concomitant IgA1 and IgA2 glomerular deposits and poor clinical outcome.

Psoriatic arthritis and onycholysis -- results from the cross-sectional Reykjavik psoriatic arthritis study.

OBJECTIVE: To measure the associations between subtypes of nail changes and psoriatic arthritis (PsA) among patients with psoriasis. METHODS: Patients age 18 years and older with active psoriasis were examined for skin and nail changes and asked if they had been diagnosed with PsA. Patients with arthritis were invited for a separate study 1-6 years after their initial visit. Univariate and multivariate analyses were used to test the strength of associations between subtypes of nail changes and arthritis. RESULTS: Of 1116 patients with psoriasis, 37% (95% CI 34%-40%) had nail changes. Age, any nail change, onycholysis, and pitting were each associated with PsA on univariate analysis. Multivariate analysis showed that onycholysis was the only type of nail change independently associated with PsA (OR 2.05, p < 0.001). Nail changes persisted and had increased in prevalence at the followup examination at a mean of 3.8 (median 4 yrs, interquartile range 3-4) years later. Previously reported associations between psoriasis location and arthritis were not seen in this dataset. CONCLUSION: PsA is associated with onycholysis. Associations with pitting and subungual hyperkeratosis were not statistically significant. Subtypes of nail changes should be analyzed separately in future studies of PsA.

Improvement of psoriasis after tonsillectomy is associated with a decrease in the frequency of circulating T cells that recognize streptococcal determinants and homologous skin determinants.

Exacerbation of chronic psoriasis can be associated with streptococcal throat infections, and T cells that respond to peptide sequences common to streptococcal M proteins and skin keratins have been detected in patients' blood. To our knowledge, we have conducted the first blinded, prospective study to assess the impact of tonsillectomy on psoriasis. Twenty-nine patients with chronic psoriasis and history of exacerbation after sore throat were randomly assigned to tonsillectomy (n = 15) or control (n = 14) groups and monitored for 2 y clinically and by enumeration of circulating skin homing T cells that respond to short homologous M protein or keratin peptides. Thirteen patients (86%) showed sustained improvement after tonsillectomy ranging from 30 to 90% reduction in disease severity. Furthermore, there was a close correlation between the degree of clinical improvement in individual patients and reduction in the frequency of peptide-reactive skin-homing T cells in their circulation. No corresponding clinical or immunologic changes were observed among the controls. These findings indicate that tonsillectomy may have a beneficial effect on chronic psoriasis because the palatine tonsils generate effector T cells that recognize keratin determinants in the skin.

A long-term follow-up of allergic diseases in Iceland.

INTRODUCTION: Allergic disorders are an increasing health problem in many countries, in particular among children. We have evaluated the prevalence and manifestations of allergy in a cohort of young Icelanders for more than two decades. Variations in the epidemiology and clinical expression of allergy in different communities may help to identify etiological factors contributing to these disorders. METHODS: A cohort of 179 children has been monitored for allergic manifestations for two decades, at the ages of two, four, eight, and 15 years, and most recently at the age of 21 years involving 120 of the participants. RESULTS: Cumulative prevalences of 40%, 45%, and 29% have been observed, respectively, for rhinoconjunctivitis, eczema, and asthma during the study period. None had developed rhinoconjunctivitis at the age of about 2 years, but the point prevalence gradually increased to 33% at the age of 21 years. Conversely, the prevalence of eczema was 31% at the age of 2 years, but gradually declined to 8% at the age of 21 years. The prevalence of asthma peaked at 28% at the age of 4 years, but declined thereafter and has remained stable at about 13% from the age of eight to 21 years. DISCUSSION: The prevalence of allergic diseases is high in Iceland among children and young individuals. Asthma and atopic eczema are very common in childhood, but decreases with age while the prevalence of rhinoconjunctivitis increases markedly. The very high and increasing prevalence of rhinoconjunctivitis among 15- to 21-year-old individuals is noteworthy.

The anti-microbial peptide LL-37 modulates immune responses in the palatine tonsils where it is exclusively expressed by neutrophils and a subset of dendritic cells.

Antimicrobial peptides are essential elements of epithelial defense against invading micro-organisms. The palatine tonsils are positioned at the entry of the airway and the gut and as such are ideally situated to act as immune sentinels in the pharynx protecting against microbial invasion. Tonsils express a number of antimicrobial peptides including hCAP18/LL-37. Here we clearly define the expression of hCAP18/LL-37 in the tonsils showing unequivocally that hCAP18/LL-37 is mainly expressed by infiltrating neutrophils and follicular CD11c+CD13+HLA-DR+ dendritic cells, rarely by macrophages, and never by the epithelium itself. To explore possible functions for follicle-derived LL-37, we stimulated tonsil mononuclear cells with LL-37 in vitro and observed the secretion of the proinflammatory cytokines CCL5 and CXCL9, expression of IFN-γ and MX-1 and down-regulation of chemokine receptors CCR4 and CCR6 which are involved in tissue-selective T cell trafficking. Taken together, these data illustrate new potential immunoregulatory functions for hCAP18/LL-37 in the tonsils.

Mannan Binding Lectin (MBL) genotypes coding for high MBL serum levels are associated with rheumatoid factor negative rheumatoid arthritis in never smokers.

INTRODUCTION: Previous studies have provided inconsistent results on whether variants in the MBL2 gene, coding for the complement-activating mannan-binding lectin (MBL) protein, associate with rheumatoid arthritis (RA). We re-evaluated this in context of the main environmental and genetic risk factors (smoking, HLA-DRB1 'shared epitope' (SE), PTPN22*620W), which predispose to rheumatoid factor (RF) and/or anti-citrullinated-protein antibody (ACPA)-positive RA. METHODS: In this population-based EIRA study, rheumatoid factor (RF), ACPA, smoking, SE and PTPN22*620W status was determined in incident RA cases and matched controls. MBL-high (n = 1330) and MBL-low (n = 1257) genotypes predicting MBL levels were constructed from four promoter and exon-1 polymorphisms in the MBL2 gene. Odds ratios with 95% confidence interval (OR, 95% CI) were calculated by logistic regression. In extended families (n = 316), previously reported data were re-analyzed, considering RF and smoking. RESULTS: MBL-high genotypes tended to be associated with RF-negative (OR = 1.20, 95% CI 0.96-1.51) but not RF-positive (OR = 1.00, 95% CI 0.83-1.20) RA. Results divided by ACPA status did not differ. When stratified for smoking, MBL-high genotype was strongly associated with RF-negative RA in never smokers (OR = 1.82, 95% CI 1.24-2.69) but not in ever smokers (OR = 0.96, 95% CI 0.73-1.30). In never smokers, the association was observed in both the RF-negative/ACPA-negative (OR = 1.67, 95% CI 1.10-2.55) and RF-negative/ACPA-positive subgroups (OR = 3.07, 95% CI 1.37-6.89), and remained on an SE/PTPN22*620W negative background. In the extended families, the reported association between high MBL and RA was in fact confined to never smokers. CONCLUSIONS: High MBL may predispose to RF-negative RA but only in individuals who have never smoked. This illustrates the importance of phenotypic subgrouping in genetic studies.

Effect of rheumatoid factor on mortality and coronary heart disease.

OBJECTIVE: An association between rheumatoid factor (RF) and increased mortality has been described in individuals with rheumatoid arthritis. The objective of this study was to determine the effect of RF on mortality and coronary heart disease (CHD) in the general population. SUBJECTS: were participants in a population-based study focused on cardiovascular disease who attended for a study visit during the years 1974-84. RF was measured and information obtained on cardiovascular risk factors, joint symptoms and erythrocyte sedimentation rate (ESR). The subjects were followed with respect to mortality and incident CHD through 2005. Adjusted comparison of overall survival and CHD event-free survival in RF-positive versus RF-negative subjects was performed using Cox proportional hazards regression models. RESULTS: Of 11 872 subjects, 140 had positive RF. At baseline RF was associated with diabetes mellitus and smoking and inversely associated with serum cholesterol. RF-positive subjects had increased all-cause mortality (HR 1.47, 95% CI 1.19 to 1.80) and cardiovascular mortality (HR 1.57, 95% CI 1.15 to 2.14) after adjusting for age and sex. Further adjustment for cardiovascular risk factors and ESR only modestly attenuated this effect. An increase in CHD among the RF-positive subjects did not reach statistical significance (HR 1.32, 95% CI 0.96 to 1.81, adjusted for age and sex). Subjects with RF but without joint symptoms also had increased overall mortality and cardiovascular mortality (HR for overall mortality 1.33, 95% CI 1.01 to 1.74, after adjustment). CONCLUSION: In a general population cohort, RF was associated with increased all-cause mortality and cardiovascular mortality after adjustment for cardiovascular risk factors, even in subjects without joint symptoms.

Psoriasis--as an autoimmune disease caused by molecular mimicry.

Psoriasis is strongly associated with streptococcal throat infection, and patients have increased occurrence of such infections. Psoriatic lesional T cells are oligoclonal, and T cells recognizing determinants common to streptococcal M-protein and keratin have been detected in patients' blood. We propose that CD8(+) T cells in psoriatic epidermis respond mainly to such determinants, whereas CD4(+) T cells in the dermis preferentially recognize determinants on the streptococcal peptidoglycan that might itself act as an adjuvant. The streptococcal association might reflect the concurrence of superantigen production promoting skin-homing of tonsil T cells, M-protein mimicking keratin determinants, and adjuvant effects of the peptidoglycan. Accordingly, improvement of psoriasis after tonsillectomy should be associated with fewer T cells that recognize keratin and streptococcal determinants.

Association of three systemic lupus erythematosus susceptibility factors, PD-1.3A, C4AQ0, and low levels of mannan-binding lectin, with autoimmune manifestations in Icelandic multicase systemic lupus erythematosus families.

OBJECTIVE: To study autoimmune diseases and autoantibodies in Icelandic multicase systemic lupus erythematosus (SLE) families and to determine the association of 3 SLE susceptibility factors, PD-1.3A, C4AQ0, and low levels of mannan-binding lectin (MBL), with autoimmune disease in this population. METHODS: Eight SLE multicase families were studied, comprising a total of 124 family members (23 patients with SLE and 101 relatives). The diagnosis of an autoimmune disease was established and autoantibodies were measured in each family. In addition, PD-1.3A alleles were genotyped, and C4AQ0 allotypes were established by electrophoresis and haplotype analysis. Low levels of MBL were determined using enzyme-linked immunosorbent assay and variant-allele genotyping. RESULTS: In the SLE multicase families there was a high frequency of other autoimmune diseases (32.2%) and a high frequency of autoantibodies (53.2%). Of all family members, 59.7% were determined to have SLE, other autoimmune diseases, antinuclear antibodies, and/or other autoantibodies. The families showed genetic heterogeneity for PD-1.3A, C4AQ0, and low MBL levels; the frequency of each factor ranged from 0% to 85%. The frequencies of PD-1.3A and C4AQ0 were significantly increased in patients with SLE, relatives with other autoimmune diseases, and non-autoimmune disease relatives compared with controls. In the 7 families whose members had low levels of MBL, this factor was significantly associated with SLE, but the frequency of low MBL was decreased in relatives with other autoimmune diseases as compared with non-autoimmune disease relatives and controls. There were indications of an additive effect, and 91% of patients with SLE, 78% of relatives with other autoimmune diseases, and 75% of non-autoimmune disease relatives carried at least 1 of the 3 factors. CONCLUSION: These results demonstrate a high frequency of autoimmune diseases and autoantibodies in SLE multicase families. PD-1.3A and C4AQ0 are part of a predisposing genetic background. Other genetic and/or environmental factors are necessary for disease expression, demonstrated by a high frequency of PD-1.3A and C4AQ0 in non-autoimmune disease relatives. Low MBL levels may be one such contributing factor. The results of this study provide an example of epistatic genetic effects and overlapping genetics in autoimmune diseases.

Low serum mannose-binding lectin level increases the risk of death due to pneumococcal infection.

BACKGROUND: Previous studies have shown associations between low mannose-binding lectin (MBL) level or variant MBL2 genotype and sepsis susceptibility. However, MBL deficiency has not been rigorously defined, and associations with sepsis outcomes have not been subjected to multivariable analysis. METHODS: We reanalyzed MBL results in a large cohort with use of individual data from 4 studies involving a total of 1642 healthy control subjects and systematically defined a reliable deficiency cutoff. Subsequently, data were reassessed to extend previous MBL and sepsis associations, with adjustment for known outcome predictors. We reanalyzed individual data from 675 patients from 5 adult studies and 1 pediatric study of MBL and severe bacterial infection. RESULTS: XA/O and O/O MBL2 genotypes had the lowest median MBL concentrations. Receiver operating characteristic analysis revealed that an MBL cutoff value of 0.5 microg/mL was a reliable predictor of low-producing MBL2 genotypes (sensitivity, 82%; specificity, 82%; negative predictive value, 98%). MBL deficiency was associated with increased likelihood of death among patients with severe bacterial infection (odds ratio, 2.11; 95% confidence interval, 1.30-3.43). In intensive care unit-based studies, there was a trend toward increased risk of death among MBL-deficient patients (odds ratio, 1.58; 95% confidence interval, 0.90-2.77) after adjustment for Acute Physiology and Chronic Health Enquiry II score. The risk of death was increased among MBL-deficient patients with Streptococcus pneumoniae infection (odds ratio, 5.62; 95% confidence interval, 1.27-24.92) after adjustment for bacteremia, comorbidities, and age. CONCLUSIONS: We defined a serum level for MBL deficiency that can be used with confidence in future studies of MBL disease associations. The risk of death was increased among MBL-deficient patients with severe pneumococcal infection, highlighting the pathogenic significance of this innate immune defence protein.

The pharmacokinetic profile of plasma-derived mannan-binding lectin in healthy adult volunteers and patients with Staphylococcus aureus septicaemia.

Mannan-binding lectin (MBL) is a member of the innate immune system, and MBL-deficiency affects 10-15% of Caucasians. With development of a plasma-derived MBL, substitution has become a therapeutic option in diseases associated with MBL insufficiency. The pharmacokinetics of injected MBL is weakly described, particularly in patients with infectious diseases. The pharmacokinetic profile of MBL following administration of 0.08 mg/kg to 20 healthy MBL-deficient volunteers and 0.2 mg/kg to 2 patients with Staphylococcus aureus septicaemia was established. In the volunteers, the maximal concentration was 2849 microg/l; the mean half-life (T(1/2)) was 69.6 h (14.6-114.9 h). The normalized clearance was 9x10(-6) l/minxkg, and the mean residence time was 82 h. In the patients the serum-MBL versus time curves were similar to those in the volunteers, and T(1/2) values were 36 and 40 h. In conclusion, MBL is distributed into a median volume of 3.4 l similar to the plasma volume, and the elimination in septicaemic patients was within the range of the controls. Due to the large individual variation in T(1/2), we recommend that MBL therapy, with respect to dose and infusion intervals, is based on the chosen therapeutic target (> or =1000 microg/l) and MBL serum determinations following the first infusion.

The genetic basis of psoriasis.

For a complex genetic disease, psoriasis has a high penetration within families and a concordance rate of up to 70% in identical twins. Despite this and the endeavors of many research groups for more than a decade, no susceptibility allele has so far been unequivocally identified, although about 20 genetic loci associated with psoriasis have been reported from linkage-based studies. Moreover, only 1 of these linkage-based loci, PSORS1, that includes the HLA-C gene on chromosome 6p21, has been universally confirmed. Very recent data strongly indicate that HLA-Cw*0602 is the susceptibility allele in this locus, a finding that is consistent with the notion that the pathogenesis of psoriasis involves autoantigen recognition by epidermal CD8+ T lymphocytes. Several candidate genes in some of the other 7 PSORS designated loci are currently being evaluated. The relative lack of success in elucidating the genetic basis of psoriasis highlights the formidable challenge of dissecting the genetic basis of diseases with a complex mode of inheritance.

Psoriatic arthritis in Reykjavik, Iceland: prevalence, demographics, and disease course.

OBJECTIVE: To determine the prevalence, demographics, and course of psoriatic arthritis (PsA) in the Reykjavik area of Iceland. METHODS: In total 220 patients >/= 18 years of age living in the Reykjavik area of Iceland were located in a community registry of psoriatic patients and in hospital records. Of these, 156 (71%) were interviewed and examined for verification of skin and joint disease according to published criteria. RESULTS: Prevalence of PsA in the adult population was estimated to be 164 per 100,000 (95% CI 143-187), adjusted to 139 per 100,000 (95% CI 112-169) after exclusion of 25 individuals. The female to male ratio was close to 2:1. The mean age at skin disease onset was 23 years, with significantly earlier onset in women (age 20 yrs in women vs 26 yrs in men; p = 0.01), but there was no significant difference for age at the time of onset of joint disease. Mean duration of PsA was 20 years. Oligoarthritis was the most common (44%), followed by polyarthritis (31%), enthesitis (8%), and inflammatory back pain (7%). According to patients' recall of clinical features at onset, 78 patients (60%) had changed categories of PsA at the time of the study, most frequently from polyarthritis to oligoarthritis (48%), followed by oligoarthritis to polyarthritis (36%). These changes seemed independent of use of disease modifying drugs, which 54% had received. CONCLUSION: PsA in Reykjavik, Iceland, has a prevalence of at least 0.14% and is strikingly more common in women. The majority of patients reported a change in the pattern of affected joints during the course of their disease.

Patients with rheumatoid arthritis have higher levels of mannan-binding lectin than their first-degree relatives and unrelated controls.

OBJECTIVE: Mannan-binding lectin (MBL) is present in serum and synovial fluid; its levels vary widely, and the variations are strongly associated with polymorphisms in the MBL2 gene. Studies have compared MBL in patients with rheumatoid arthritis (RA) and in unrelated controls, but the findings have been contradictory. In the first family-based study, we compared MBL levels in patients with RA to population controls and also to their nonaffected first-degree relatives, who may be regarded as optimal controls because of less genetic variation. METHODS: Serum levels of MBL and rheumatoid factor were analyzed in 210 patients with RA and 406 of their first-degree relatives from 74 extended families. Population controls for MBL levels were 330 randomly selected adult Icelanders. RESULTS: Patients with RA had higher MBL levels in serum (median 1553 microg/l) than their first-degree relatives (1073 microg/l; p = 0.003) and the unrelated controls (938 microg/l; p < 0.0001). No association was found between MBL and rheumatoid factor. CONCLUSION: Patients with RA had markedly higher MBL levels than their close relatives and controls, indicating that high MBL may predispose to RA. As MBL has been shown to bind potential arthritogenic agents including modified immunoglobulins, cellular debris, and microorganisms, our findings suggest that high MBL could trigger complement mediated inflammation within joints.

Mouse models of psoriasis.

Psoriasis is a T-cell-mediated chronic inflammatory skin disease believed to be of autoimmune nature that can be triggered or worsened by streptococcal throat infections. In addition to conventional chronic inflammatory changes, psoriasis is characterized by complex and striking alterations in epidermal growth and differentiation. Psoriasis is generally not observed in animals other than man, and this lack of a suitable animal model has greatly hindered research into the pathogenesis of psoriasis. Multiple transgenic, knockout, and reconstituted models of psoriasis have been developed over the past two decades. Despite their limitations, these models have demonstrated that keratinocyte hyperplasia, vascular hyperplasia, and cell-mediated immunity in the skin are closely interrelated. Xenograft models, in which involved and uninvolved psoriatic skin are transplanted onto immunodeficient mice, are the only models that come close to incorporating the complete genetic, immunologic, and phenotypic changes of the disease. They have shown conclusively that psoriasis is a T-cell-mediated disease, and have been used to elucidate novel pathogenic pathways. In this review, we describe various animal models, detail the immunologic and intracellular pathways that mediate these phenotypes and assess the utility of these models to better understand this disease.

Distinct clinical differences between HLA-Cw*0602 positive and negative psoriasis patients--an analysis of 1019 HLA-C- and HLA-B-typed patients.

A major susceptibility gene for psoriasis is located in the major histocompatibility complex class I region on chromosome 6 very close to the HLA-Cw6 gene. We collected a cohort of 1,019 patients with chronic plaque psoriasis. The patients were typed for HLA-C and HLA-B. A total of 654 (64.2%) were HLA-Cw*0602 positive but 365 (35.8%) carried other HLA-C alleles. We confirmed that HLA-Cw*0602 positive patients have younger age of onset (17.5 vs 24.3 years, P<10(-10)), higher incidence of guttate and the eruptive type of psoriasis (P<0.0001), more frequent exacerbations with throat infections (P=0.01), higher incidence of the Koebner's phenomenon (P=0.01), and more extensive disease (P=0.03). A striking new finding was a diverging pattern of disease severity in HLA-Cw*0602 positive and negative patients depending on the age of onset of the disease (P=0.0006). HLA-Cw*0602 positive women also had more frequent remissions during pregnancy (P<0.0001). All types of nail changes were, however, more common in the Cw*0602 negative patients (P=0.003) and they more often had multiple types of nail lesions (P<0.0001). The three ancestral haplotypes of Cw*0602 all conferred an increase in odds ratio but showed no difference in any of the clinical features studied. Our findings indicate that the genetic factor on chromosome 6 has a strong influence on the phenotype of the disease, and underline that differences in clinical features of psoriasis may be to a large extent genetically determined.