Non-autoimmune Diseases Research Articles

Galectin‐9 expands immunosuppressive macrophages to ameliorate T‐cell‐mediated lung inflammation

Galectin-9 (Gal-9) plays pivotal roles in the modulation of innate and adaptive immunity to suppress T-cell-mediated autoimmune models. However, it remains unclear if Gal-9 plays a suppressive role for T-cell function in non-autoimmune disease models. We assessed the effects of Gal-9 on experimental hypersensitivity pneumonitis induced by Trichosporon asahii. When Gal-9 was given subcutaneously to C57BL/6 mice at the time of challenge with T. asahii, it significantly suppressed T. asahii-induced lung inflammation, as the levels of IL-1, IL-6, IFN-gamma, and IL-17 were significantly reduced in the BALF of Gal-9-treated mice. Moreover, co-culture of anti-CD3-stimulated CD4 T cells with BALF cells harvested from Gal-9-treated mice on day 1 resulted in diminished CD4 T-cell proliferation and decreased levels of IFN-gamma and IL-17. CD11b(+)Ly-6C(high)F4/80(+) BALF Mphi expanded by Gal-9 were responsible for the suppression. We further found in vitro that Gal-9, only in the presence of T. asahii, expands CD11b(+)Ly-6C(high)F4/80(+) cells from BM cells, and the cells suppress T-cell proliferation and IFN-gamma and IL-17 production. The present results indicate that Gal-9 expands immunosuppressive CD11b(+)Ly-6C(high) Mphi to ameliorate Th1/Th17 cell-mediated hypersensitivity pneumonitis.

Disease-specific definitions of vitamin D deficiency need to be established in autoimmune and non-autoimmune chronic diseases: a retrospective comparison of three chronic diseases

IntroductionWe compared the odds of vitamin D deficiency in three chronic diseases: systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and type 2 diabetes (T2DM), adjusting for medications, demographics, and laboratory parameters, common to all three diseases. We also designed multivariate models to determine whether different factors are associated with vitamin D deficiency in different racial/ethnic groups.MethodsWe identified all patients with non-overlapping diagnoses of SLE, RA, and T2DM, with 25-hydroxyvitamin D (25OHD) levels measured between 2000 and 2009. Vitamin D deficiency was defined as 25OHD levels <20 ng/ml, based on previously established definitions. Race/ethnicity was analyzed as African-American non-Hispanic (African-American), Hispanic non-African-American (Hispanic), and Other based on self report.ResultsWe included 3,914 patients in the final analysis: 123 SLE, 100 RA, and 3,691 T2DM. Among African-Americans the frequency of vitamin D deficiency was 59% in SLE, 47% in RA, and 67% in T2DM. Among Hispanics the frequency of vitamin D deficiency was 67% in SLE, 50% in RA, and 59% in T2DM. Compared with the SLE group, the adjusted odds ratio of vitamin D deficiency was 1.1, 95% CI (0.62, 2.1) in the RA group, and 2.0, 95% CI (1.3, 3.1) in the T2DM group. In the multivariate analysis, older age, higher serum calcium and bisphosphonate therapy were associated with a lower odds of vitamin D deficiency in all three racial/ethnic groups: 1,330 African-American, 1,257 Hispanic, and 1,100 Other. T2DM, serum creatinine, and vitamin D supplementation were associated with vitamin D deficiency in some, but not all, racial/ethnic groups.ConclusionsVitamin D deficiency is highly prevalent in our patients with SLE, RA, and T2DM. While the odds of vitamin D deficiency are similar in RA and SLE patients in a multivariate analysis, T2DM patients have much higher odds of being vitamin D deficient. Different demographic and laboratory factors may be associated with vitamin D deficiency within different racial/ethnic groups. Therefore, disease-specific and race/ethnicity-specific definitions of vitamin D deficiency need to be established in future studies in order to define goals of vitamin D replacement in patients with autoimmune and non-autoimmune chronic diseases.

Genetic defects, thyroid growth and malfunctions of the TSHR in pediatric patients

Naturally occurring activating and inactivating mutations of the thyrotropin receptor (TSHR) were found as a molecular cause of diseases in patients suffering from non-autoimmune hyperthyroidism and syndromes of thyrotropin resistance, respectively. These mutations are mostly functionally characterized in vitro and therefore, they represent an excellent tool to study structure-function relationships of this G-protein-coupled receptor. In this review, we summarize published germline mutations of the TSHR with focus on 1) the phenotype of (pediatric) patients, 2) potential genotype/phenotype correlations, 3) structural implications for receptor activation and inactivation, 4) the impact on thyroid growth, and 5) finally on aspects of TSHR dimerization. In conclusion, this comprehensive analysis of medical and biological data opens an avenue to understand genetic defects and malfunctions of the TSHR in molecular detail and in their entirety. This knowledge is important to refine our insights in non-autoimmune diseases caused by defects of the TSHR gene and it might help to develop pharmacological means for compensation of uncontrolled thyroid growth.

Primary liver transplantation for autoimmune hepatitis: A comparative analysis of the European Liver Transplant Registry

The principal aim of this study was to compare the probability of and potential risk factors for death and graft loss after primary adult and pediatric liver transplantation in patients undergoing transplantation for autoimmune hepatitis (AIH) to those in patients undergoing transplantation for primary biliary cirrhosis (PBC; used as the reference group) or alcoholic cirrhosis (used as an example of a nonautoimmune liver disease). The 5-year survival of patients undergoing transplantation for AIH (n = 827) was 0.73 [95% confidence interval (CI) = 0.67-0.77]. This was similar to that of patients undergoing transplantation for alcoholic cirrhosis (0.74, 95% CI = 0.72-0.76, n = 6424) but significantly worse than that of patients undergoing transplantation for PBC (0.83, 95% CI = 0.80-0.85, n = 1588). Fatal infectious complications occurred at an increased rate in patients with AIH (hazard ratio = 1.8, P = 0.002 with PBC as the reference). The outcome of pediatric AIH patients was similar to that of adult patients undergoing transplantation up to the age of 50 years. However, the survival of AIH patients undergoing transplantation beyond the age of 50 years (0.61 at 5 years, 95% CI = 0.51-0.70) was significantly reduced in comparison with the survival of young adult AIH patients (0.78 at 18-34 years, 95% CI = 0.70-0.86) and in comparison with the survival of patients of the same age group with PBC or alcoholic cirrhosis. In conclusion, age significantly affects patient survival after liver transplantation for AIH. The increased risk of dying of infectious complications in the early postoperative period, especially above the age of 50 years, should be acknowledged in the management of AIH patients with advanced-stage liver disease who are listed for liver transplantation. It should be noted that not all risk factors relevant to patient and graft survival could be analyzed with the European Liver Transplant Registry database.

Autoimmune disease classification by inverse association with SNP alleles.

With multiple genome-wide association studies (GWAS) performed across autoimmune diseases, there is a great opportunity to study the homogeneity of genetic architectures across autoimmune disease. Previous approaches have been limited in the scope of their analysis and have failed to properly incorporate the direction of allele-specific disease associations for SNPs. In this work, we refine the notion of a genetic variation profile for a given disease to capture strength of association with multiple SNPs in an allele-specific fashion. We apply this method to compare genetic variation profiles of six autoimmune diseases: multiple sclerosis (MS), ankylosing spondylitis (AS), autoimmune thyroid disease (ATD), rheumatoid arthritis (RA), Crohn's disease (CD), and type 1 diabetes (T1D), as well as five non-autoimmune diseases. We quantify pair-wise relationships between these diseases and find two broad clusters of autoimmune disease where SNPs that make an individual susceptible to one class of autoimmune disease also protect from diseases in the other autoimmune class. We find that RA and AS form one such class, and MS and ATD another. We identify specific SNPs and genes with opposite risk profiles for these two classes. We furthermore explore individual SNPs that play an important role in defining similarities and differences between disease pairs. We present a novel, systematic, cross-platform approach to identify allele-specific relationships between disease pairs based on genetic variation as well as the individual SNPs which drive the relationships. While recognizing similarities between diseases might lead to identifying novel treatment options, detecting differences between diseases previously thought to be similar may point to key novel disease-specific genes and pathways.

P-ANCAs in autoimmune liver disorders recognise human β-tubulin isotype 5 and cross-react with microbial protein FtsZ

ObjectiveAutoimmune hepatitis and primary sclerosing cholangitis are chronic inflammatory disorders of unknown aetiology, frequently associated with the presence of perinuclear antineutrophil cytoplasmic antibodies (p-ANCAs) directed against an unknown antigen of...

Leptin in Non-Autoimmune Inflammation

Leptin is an adipokine that modulates multiple functions including energy homeostasis, thermoregulation, bone metabolism, endocrine and pro-inflammatory immune responses. Several studies have implicated leptin in the pathogenesis of chronic autoimmune inflammatory conditions such as autoimmune encephalomyelitis, intestinal bowel inflammation and type-1 diabetes. This review focuses on the role of leptin in non-autoimmune inflammatory diseases that include renal, liver and lung inflammation, atherosclerosis and metabolic syndrome, Behçet's disease and endometriosis.

The Ped-APS Registry: the antiphospholipid syndrome in childhood

In recent years, antiphospholipid syndrome (APS) has been increasingly recognised in various paediatric autoimmune and nonautoimmune diseases, but the relatively low prevalence and heterogeneity of APS in childhood made it very difficult to study in a systematic way. The project of an international registry of paediatric patients with APS (the Ped-APS Registry) was initiated in 2004 to foster and conduct multicentre, controlled studies with large number of paediatric APS patients. The Ped-APS Registry is organised as a collaborative project of the European Forum on Antiphospholipid Antibodies and Juvenile Systemic Lupus Erythematosus Working Group of the Paediatric Rheumatology European Society. Currently, it documents a standardised clinical, laboratory and therapeutic data of 133 children with antiphospholipid antibodies (aPL)-related thrombosis from 14 countries. The priority projects for future research of the Ped-APS Registry include prospective enrollment of new patients with aPL-related thrombosis, assessment of differences between the paediatric and adult APS, evaluation of proinflammatory genotype as a risk factor for APS manifestations in childhood and evaluation of patients with isolated nonthrombotic aPL-related manifestations.

Evaluation of the autoimmune regulator (AIRE) gene mutations in a cohort of Italian patients with autoimmune‐polyendocrinopathy‐candidiasis‐ectodermal‐dystrophy (APECED) and in their relatives

Autoimmune-polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED) is a rare syndrome characterized by chronic candidiasis, chronic hypoparathyroidism and Addison's disease. APECED has been associated with mutations in autoimmune regulator (AIRE) gene. Our aim is to perform a genetic analysis of the AIRE gene in Italian APECED patients and in their relatives. Design AIRE mutations were determined by DNA sequencing in all subjects. Patients were tested for clinical autoimmune or non-autoimmune diseases, or for organ and non-organ specific autoantibodies. A total of 24 Italian patients with APECED (15 from the Venetian region, 2 from Southern-Tyrol, 4 from Apulia, 3 from Sicily), 25 relatives and 116 controls were studied. Ten out of the 15 Venetian patients (66%) were homozygous for R257X or compound heterozygous with 1094-1106del13. One patient was homozygous for 1094-1106del13 and another for R139X. A novel mutation (1032-1033delGT) in combination with 1094-1106del13 was identified in one patient. No mutations were found in two cases. Two patients from Southern Tyrol were homozygous for R257X and for 1094-1106del13bp. All patients from Apulia were homozygous or heterozygous for W78R combined with Q358X. The patients from Sicily were homozygous for R203X or compound heterozygous with R257X. The analysis of the genotype-phenotype revealed that patients carrying 1094-1106del13 at the onset of Addison's disease were significantly older than those carrying other mutations. The genetic study of 25 relatives identified 20 heterozygous subjects. They suffered from various autoimmune and non-autoimmune diseases but no major disease of APECED was found. These data demonstrate the great genetic heterogeneity for the AIRE mutations in Italian APECED patients, and that the heterozygosity for AIRE mutations do not produce APECED.

Fetal microchimerism and maternal health during and after pregnancy.

Trafficking of fetal cells into the maternal circulation begins very early in pregnancy and the effects of this cell traffic are longlasting. All types of fetal cells, including stem cells, cross the placenta during normal pregnancy to enter maternal blood, from where they may be recovered in pregnancy for the purpose of genetic prenatal diagnosis. Fetal cells can also be located in maternal tissues during and after pregnancy, and persist as microchimeric cells for decades in marrow and other organs. Although persistent fetal cells were first implicated in autoimmune disease, subsequent reports routinely found microchimeric cells in healthy tissues and in non-autoimmune disease. Parallel studies in animal and human pregnancy now suggest instead that microchimeric fetal cells play a role in the response to tissue injury. However, it is still not clear whether microchimeric fetal cells persisting in the mother are an incidental finding, are naturally pathogenic or act as reparative stem cells, and the environmental or biological stimuli that determine microchimeric cell fate are as yet undetermined. Future studies must also focus on investigating whether fetal cells create functional improvement in response to maternal injury and whether this response can be manipulated. The pregnancy-acquired low-grade chimeric state of women could have far-reaching implications, influencing recovery after injury or surgery, ageing, graft survival after transplantation, survival after cancer as well as deciding the protective effect of pregnancy against diseases later in life. Lifelong persistence of fetal cells in maternal tissues may even explain why women live longer than men.

UV Radiation Regulates Mi-2 through Protein Translation and Stability

Dermatomyositis (DM) is an autoimmune disease, which is often accompanied by the development of disease-specific autoantibodies directed against the SNF2-superfamily helicase, Mi-2. Recent evidence suggests that ultraviolet radiation exposure may be an important risk factor for the development of not only the disease but also specific autoimmunity against Mi-2. Consequently, we investigated the effects of ultraviolet radiation on Mi-2 protein expression. We observed an increase in protein levels upon ultraviolet radiation exposure in cell culture systems. These changes in expression occur quite rapidly, are maximized just 1 h following exposure, and are unique to Mi-2 when compared with other members of the NuRD complex. Changes in protein levels are not mediated through transcriptional mechanisms. Treatment results in a more efficiently translated message through regulatory elements in the 5'-UTR region of the transcript. Investigation into protein half-life further demonstrated increased stability of Mi-2 following UV exposure. Taken together, we describe a system by which Mi-2 protein expression can be quickly increased following UV exposure and then maintained up to 16 h later. These data provide a novel regulation of an important transcriptional regulator and provide insight into the possible mechanisms of the development of DM and associated autoantibodies.

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

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. 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. 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. 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.

Significance of extractable nuclear antigens in childhood autoimmune liver disease.

Antinuclear antibody (ANA) is found in connective tissue disorders and in autoimmune liver disease. While ANA-positive connective tissue disorders are subdivided according to possession of specific antibodies to extractable nuclear antigens (ENA) (anti-ribonucleoprotein (anti-RNP), anti-Smith (anti-Sm), anti-Ro, anti-La), little is known about the presence and significance of ENA in autoimmune liver disease. To investigate this, we have tested 35 children with autoimmune hepatitis (AIH) (19 ANA and/or smooth muscle antibody-positive (ANA/SMA+ve); 16 liver kidney microsomal 1-positive (LKM-1 + ve)) and 14 with ANA/SMA+ve autoimmune sclerosing cholangitis (ASC), using both double dimension immunodiffusion and ELISAs. Eighty children with non-autoimmune liver disease (20 alpha 1-antitrypsin deficiency, 20 Wilson's disease, 20 Alagille's syndrome and 20 chronic hepatitis B virus infection) and 20 healthy controls were also tested. ENA were detected in seven (20%) patients with AIH: two ANA-positive, one SMA-positive and four LKM-1-positive. Three were positive for anti-Sm, two for anti-La, one for anti-Sm/anti-La and one for anti-Sm/anti-La/anti-Ro. ENA-positive had more severe liver disease than ENA-negative patients (P < 0.03). ENA were not detected in ASC, non-autoimmune liver diseases and controls. Our results indicate that ENA reactivity, including anti-Sm and anti-La, characteristic of systemic lupus erythematosus and Sjögren's syndrome, respectively, are present in some patients with AIH even in the absence of ANA, and may characterize a particularly severe form of the disease.

Detection of transforming growth factor-beta in rheumatoid arthritis synovial tissue: lack of effect on spontaneous cytokine production in joint cell cultures

The presence of transforming growth factor-beta (TGF-beta) in inflammatory joint disease was investigated. Synovial fluid from patients with rheumatoid arthritis (RA) and patients with other non-autoimmune inflammatory joint diseases contained high levels of both active and latent TGF-beta. Levels of active TGF-beta did not correlate with drug regimen in either patient group or with the recovery period in the individuals with non-RA joint disease. Freshly isolated synovial cells from individuals with RA were shown by Northern blotting to express the mRNA for TGF-beta 1 and to secrete latent TGF-beta protein which could be neutralized by antibodies to TGF-beta 1 and TGF-beta 2. Lipopolysaccharide-stimulated peripheral blood mononuclear cells from normal donors produced interleukin-1 (IL-1) and tumour necrosis factor-alpha (TNF-alpha) which was inhibited by pretreatment of these cells with recombinant TGF-beta. Cytokine production was not inhibited if the addition of TGF-beta was used after the inducing stimulus, suggesting that in activated cells cytokine production cannot be inhibited. This was confirmed by the observation that neither TGF-beta 1 or TGF-beta 2 inhibited spontaneous IL-1 or TNF-alpha production by rheumatoid synovial mononuclear cells in culture. These findings show that despite the presence of active TGF-beta in RA synovial joints and the spontaneous production of latent (potentially active) TGF-beta by RA cells in culture, additional TGF-beta did not inhibit ongoing cytokine synthesis in vitro. This suggests that TGF-beta may not inhibit cytokine production in the rheumatoid joint although it cannot be ruled out that in vivo TGF-beta already has an immunosuppressive effect which cannot be further increased in vitro by exogenous protein.

IgG subclass distribution of thyroglobulin antibodies in patients with thyroid disease.

The IgG subclass distribution of thyroglobulin antibodies (TgAb) has been studied in Hashimoto and Graves' patients by several investigators with conflicting results, in part explainable by methodological problems. We have recently developed a quantitative ELISA to measure in absolute terms the serum concentration of TgAb subclasses. The aim of the present study was to apply this method in a large series of patients with autoimmune as well as, for the first time, non-autoimmune thyroid diseases. We examined 28 patients with Hashimoto's thyroiditis, 30 with Graves' disease, 21 with thyroid carcinoma and 18 with non-toxic goitre, all selected for the presence of TgAbs. The results indicated that TgAbs in thyroid diseases were not restricted to any particular isotype, but comprised all four IgG subclasses. IgG1 was represented similarly in the four groups. The same was true for IgG3, even though its contribution to the total antibody content was very small. IgG4 was the dominant subclass in patients with Graves' disease, thyroid carcinoma and non-toxic goitre, probably reflecting a prolonged antigenic challenge. In Hashimoto's thyroiditis IgG2 was dominant, possibly because T helper lymphocytes infiltrating the thyroid are typically Th1 type.

Prominent Plasmacytosis Following Intravenous Immunoglobulin Correlates with Clinical Improvement in Guillain-Barré Syndrome

BackgroundHigh doses of pooled polyclonal IgG are commonly used to treat numerous autoimmune diseases. Their mode of action nevertheless remains only partially explained. At the same time, until now, no early biological marker has been able to predict their efficacy.Methodology/Principal FindingsIn a first pilot retrospective analysis, we reviewed white blood cell counts and blood smears in consecutive patients with autoimmune disease (n = 202) and non-autoimmune disease (n = 104). Autoimmune patients received either intravenous immunoglobulin (IVIg, n = 103), plasma exchange (n = 78) or no specific treatment (n = 21). We then prospectively monitored consecutive autoimmune patients with IVIg injection (n = 67), or without any specific treatment (n = 10) using the same routine laboratory tests, as well as flow cytometry. Both retrospective and prospective analyses identified large plasma-cell mobilization exclusively in IVIg-treated autoimmune patients 7 days after initiation of treatment. The majority of IVIg-mobilized plasma cells were immature HLA-DRhigh/CD138low/CXCR4low plasma cells expressing intracellular immunoglobulin G which were neither IVIg- nor human IgG-specific. Importantly, we found a strong negative correlation between the absolute number of IVIg-mobilized plasma cells and time to improve neurological function in both retrospective and prospective studies of Guillain-Barré syndrome (GBS), (r = −0.52, p = 0.0031, n = 30, r = −0.47, p = 0.0028, n = 40, respectively).Conclusions/SignificanceIVIg promotes immature plasma-cell mobilization in patients with GBS, chronic inflammatory demyelinating polyneuropathy, myasthenia gravis and inflammatory myopathy. Prominent day 7 plasma-cell mobilization is a favourable prognostic marker in patients with GBS receiving IVIg treatment.

EFFECT OF EXPERIMENTAL HYPERLEPTINEMIA ON PLASMA PARAOXONASE 1 (PON1) ACTIVITY TOWARD HOMOCYSTEINE THIOLACTONE AND N-HOMOCYSTEINYLATION OF PLASMA PROTEINS

Functional assessment of cholesterol efflux capacity (CEC) to high-density lipoprotein (HDL) is an emerging tool for evaluating morbidity and mortality associated with cardiovascular disease (CVD). By promoting macrophage reverse cholesterol transport (RCT), HDL-mediated CEC is believed to play an important role in atherosclerotic lesion progression in the vessel wall. Furthermore, recent evidence indicates that the typical inverse associations between various forms of CEC and CV events may be strongly modulated by environmental systemic factors and traditional CV risk factors, in addition to autoimmune diseases. These factors influence the complex and dynamic composition of HDL particles, which in turn positively or negatively affect HDL-CEC. Herein, we review recent findings connecting HDL-CEC to traditional CV risk factors and cardiometabolic conditions (non-autoimmune diseases) as well as autoimmune diseases, with a specific focus on how these factors may influence the associations between HDL-CEC and CVD risk.

Celiac disease autoantibodies in severe autoimmune liver disease and the effect of liver transplantation.

Celiac disease (CD) is associated with primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune hepatitis. We investigated the following: (i) the prevalence of tissue transglutaminase antibodies (tTGAs) and endomysial antibodies (EMAs) in end-stage autoimmune liver disease (ESALD), (ii) the correlation among auto-antibodies and the human leucocyte antigen (HLA) haplotype, and (iii) the effect of liver transplantation on antibody kinetics. Pretransplantation sera from 488 patients (310 with ESALD, and 178 with non-autoimmune disease) were tested for tTGAs. Positive samples were also tested for EMAs, and retested 6-12 and > or = 24 months post-transplantation. Results were correlated with the HLA type of the recipient. Serological evidence of CD was found in 3% (ESALD) vs. 0.6% (non-autoimmune) of the patients (five-fold increased risk in ESALD). The prevalence of tTGAs (14.2 vs. 5.4%, P=0.0001) and EMAs (4.3 vs. 0.78%, P=0.01) was significantly higher in patients with the HLA-DQ2 or HLA-DQ8 haplotypes. tTGAs and EMAs normalized in 94 and 100%, respectively, without gluten exclusion post-transplantation. Post-transplantation, of the five patients with symptoms of 'classical' CD, three improved. Intestinal lymphoma was diagnosed in another two cases with clinically 'silent' CD. Patients with ESALD, especially those who are HLA-DQ2 or HLA-DQ8 positive had a high prevalence of CD-associated antibodies. Both tTGAs and EMAs decreased post-transplantation without gluten withdrawal. Immunosuppression may improve symptoms of CD, but might not prevent progression to intestinal lymphoma.

Occurrence and Risk Factors for Autoimmune Thyroid Disease in Patients with Atrophic Body Gastritis

Purpose To investigate the occurrence of and risk factors for autoimmune thyroid disease in atrophic body gastritis patients. Methods Cross-sectional study on 401 consecutive outpatients with atrophic body gastritis. Diagnostic work-up of thyroid disease was completed in 319 atrophic body gastritis patients (225 women, median age 55.5 years [range 17-95 years]). Data on anagraphics, lifestyle, family history, and biochemical and histological items were obtained at baseline, and associations between atrophic body gastritis and autoimmune and nonautoimmune thyroid diseases were explored through descriptive statistics and logistic regression analyses. Results Of the 319 atrophic body gastritis patients, 169 (53%) had an associated thyroid disorder, and 89 (52.7%) of these were unaware of it. The thyroid disease was autoimmune in 128 patients (75.7%) and nonautoimmune in 41 patients. Logistic regression showed that risk factors for having autoimmune thyroid disease in atrophic body gastritis patients were female sex (odds ratio [OR] 5.6, 95% confidence interval [CI], 2.6-12.1), presence of parietal cell antibodies (OR 2.5, 95% CI, 1.1-5.5), and presence of metaplastic atrophy (OR 2.2, 95% CI, 1.0-5.0). Conclusions Autoimmune thyroid disease and atrophic body gastritis occur in a closely linked fashion, suggesting that atrophic body gastritis patients should be investigated for an occult autoimmune thyroid disease, in particular women and those with positive parietal cell antibodies.

The Boston Keratoprosthesis in Stevens-Johnson Syndrome

To evaluate the use of the Boston keratoprosthesis (KPro) in patients with Stevens-Johnson syndrome (SJS). Retrospective, noncomparative, interventional case series. Sixteen eyes of 15 patients with SJS underwent KPro surgery at the Massachusetts Eye and Ear Infirmary from January 2000 through December 2005. The preoperative, operative, and postoperative findings were recorded. All patients underwent either the type I or type II Boston KPro surgery by one surgeon (C.H.D.). Retention of the prosthesis, best-corrected visual acuity, the need for surgical revision, and postoperative complications were recorded. The outcomes were compared with those of an earlier group of patients from the 1990s. The mean age of patients was 50+/-18 years (range, 23 to 74 years), and the mean duration of their disease was 10+/-6.6 years. The mean follow-up period was 3.6+/-1.5 years (range, 10.2 months to 5.6 years). Ten eyes underwent type II KPro surgery, whereas six eyes underwent type I KPro surgery. Twelve eyes (75%) achieved a visual acuity of 20/200 or better after surgery, with eight eyes (50%) achieving excellent vision of 20/40 or better. Visual acuity was maintained at 20/200 or better over a mean period of 2.5+/-2.0 years. Preexisting glaucoma was found to be a significant risk factor for visual loss. There were no cases of KPro extrusion or endophthalmitis. KPro in SJS has improved, largely because of the introduction of vancomycin prophylaxis and better glaucoma treatment. It seems to be superior to standard penetrating keratoplasty, with or without allografted stem cell transplantation, as judged from the literature. However, the outcome of the KPro in SJS is still substantially less favorable than in nonautoimmune diseases.