抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.

/pdf/biological-insights-from-108-schizophrenia-associated-3rfvth8dm9.pdf

Biological insights from 108 schizophrenia-associated genetic loci

1. Introduction and Overview. 2. Detecting Influential Observations and Outliers. 3. Detecting and Assessing Collinearity. 4. Applications and Remedies. 5. Research Issues and Directions for Extensions. Bibliography. Author Index. Subject Index.

Regression Diagnostics: Identifying Influential Data and Sources of Collinearity

admission. This proportion could already be greater in some parts of the country and may increase if referrals of cases of self-poisoning increase faster than the facilities for their assessment and management. The provision of social work and psychiatric expertise in casualty departments may be one means of preventing unnecessary medical admissions without risk to the patients. Dr Blake's and Dr Bramble's figures do not demonstrate, however, that any advantage would attach to medical teams taking over assessment from psychiatrists except that, by implication, assessments would be completed sooner by staff working on the ward full time. What the figures actually suggest is that if assessment of overdoses were left to house doctors there would be an increase in admissions to psychiatric units (by 19°U), outpatients (by 5O°'), and referrals to social services (by 140o). So for house doctors to assess overdoses would provide no economy for the psychiatric or social services. The study does not tell us what the consequences would have been for the six patients who the psychiatrists would have admitted but to whom the house doctors would have offered outpatient appointments. E J SALTER

Vitamin D deficiency.

Objective The Systemic Lupus International Collaborating Clinics (SLICC) group revised and validated the American College of Rheumatology (ACR) systemic lupus erythematosus (SLE) classification criteria in order to improve clinical relevance, meet stringent methodology requirements, and incorporate new knowledge regarding the immunology of SLE. Methods The classification criteria were derived from a set of 702 expert-rated patient scenarios. Recursive partitioning was used to derive an initial rule that was simplified and refined based on SLICC physician consensus. The SLICC group validated the classification criteria in a new validation sample of 690 new expert-rated patient scenarios. Results Seventeen criteria were identified. In the derivation set, the SLICC classification criteria resulted in fewer misclassifications compared with the current ACR classification criteria (49 versus 70; P = 0.0082) and had greater sensitivity (94% versus 86%; P < 0.0001) and equal specificity (92% versus 93%; P = 0.39). In the validation set, the SLICC classification criteria resulted in fewer misclassifications compared with the current ACR classification criteria (62 versus 74; P = 0.24) and had greater sensitivity (97% versus 83%; P < 0.0001) but lower specificity (84% versus 96%; P < 0.0001). Conclusion The new SLICC classification criteria performed well in a large set of patient scenarios rated by experts. According to the SLICC rule for the classification of SLE, the patient must satisfy at least 4 criteria, including at least one clinical criterion and one immunologic criterion OR the patient must have biopsy-proven lupus nephritis in the presence of antinuclear antibodies or antidouble-stranded DNA antibodies. (Less)

/pdf/derivation-and-validation-of-the-systemic-lupus-3ua8eoavoo.pdf

Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus.

The three-dimensional organization of the genome in mammalian interphase nuclei is intrinsically linked to the regulation of gene expression. Whole chromosome territories and their encoded gene loci occupy preferential positions within the nucleus that changes according to the expression profile of a given cell lineage or stage. To further illuminate the relationship between chromosome organization, epigenetic environment, and gene expression, here we examine the functional organization of chromosome X and corresponding X-linked genes in a variety of healthy human and disease state X diploid (XX) cells. We observe high frequencies of homologous chromosome X colocalization (or coalescence), typically associated with initiation of X-chromosome inactivation, occurring in XX cells outside of early embryogenesis. Moreover, during chromosome X coalescence significant changes in Xist, H3K27me3, and X-linked gene expression occur, suggesting the potential exchange of gene regulatory information between the active and inactive X chromosomes. We also observe significant differences in chromosome X coalescence in disease-implicated lymphocytes isolated from systemic lupus erythematosus (SLE) patients compared to healthy controls. These results demonstrate that X chromosomes can functionally interact outside of embryogenesis when X inactivation is initiated and suggest a potential gene regulatory mechanism aberration underlying the increased frequency of autoimmunity in XX individuals.

/pdf/varying-levels-of-x-chromosome-coalescence-in-female-somatic-2ycd8mvw55.pdf

Varying levels of X chromosome coalescence in female somatic cells alters the balance of X-linked dosage compensation and is implicated in female-dominant systemic lupus erythematosus.

Objective. Alpha-chlorofatty acid (α-ClFA) is one product of myeloperoxidase activity in vivo during atherogenesis and may be a biomarker for cardiovascular disease (CVD). We investigated if serum α-ClFA is associated with subclinical CVD as measured by coronary artery and aorta calcium scores (CAC and AC, respectively) in women with and without systemic lupus erythematosus (SLE).

Methods. This pilot project analyzed baseline data from 173 women with SLE and 186 women without SLE participating in a 5-year longitudinal investigation of the Study of Lupus Vascular and Bone Long-term Endpoints (SOLVABLE). Data collection included demographic information, CVD and SLE risk factors, and laboratory assessments. Alpha-ClFA was measured in stored serum by liquid chromatography-mass spectrometry. CAC and AC were measured by computed tomography. Outcome measures were CAC and AC present (CAC > 0 or AC > 0) versus absent (CAC = 0 or AC = 0). Associations between risk factors and CAC or AC were tested with descriptive statistics and multivariate analyses.

Results. Women with SLE had higher α-ClFA levels than women without SLE (42.0 fmol/25 µ l ± 37.3 vs 34.5 fmol/25 µ l ± 21.9; p = 0.020). In analyses including individual CVD risk factors, having SLE was independently associated with the presence of CAC (OR 3.42, 95% CI 1.72 to 6.78) but not AC. Alpha-ClFA was not associated with the presence of CAC or AC in patients with SLE.

Conclusion. SLE, but not serum α-ClFA, was associated with the presence of CAC in this pilot project.

https://www.jrheum.org/content/jrheum/41/9/1834.full.pdf

Alpha-chlorofatty acid and coronary artery or aorta calcium scores in women with systemic lupus erythematosus. A pilot study

Autoimmune Connective Tissue Disease in Pregnancy

Erratum: The Systemic Lupus International Collaborating Clinics (SLICC) Group-It Was 20 Years Ago Today (Lupus (2011) 20 (1426-1432) DOI: 10.1177/0961203311421501)

Dear Sir, The recent paper of Parikh-Patel et al. [1] revisits the association between SLE and cancer, a phenomenon established in earlier works by other teams [2, 3]. Unfortunately, the most clinically relevant question, regarding the mechanism underlying the association between cancer and SLE, remains largely unanswered. To date, there are two large-scale studies that have shed some light on these issues. Last year, Lofstrom et al. published a case–control study presenting convincing data suggesting that disease activity plays a role in driving the risk of hematological malignancies in SLE [4]. However, that study was unable to control concomitantly for disease activity and drug exposures, two variables that are very tightly linked. The most thorough assessment of factors influencing cancer risk in SLE was conducted in a large, multi-center, clinically defined SLE cohort, with results only recently available [5]. In this study, the hazard ratio (HR) for cancer after exposure to an immunosuppressive drug was calculated, using regression models that controlled for other medications (anti-malarial drugs, systemic glucocorticoids, nonsteroidal anti-inflammatory drugs, aspirin), smoking, age, sex, race/ethnicity, geographic location, calendar year, SLE duration, and lupus damage scores. Here, the adjusted HR for overall cancer risk after any immunosuppressive drug was 0.82 (95% CI: 0.50–1.36). Considering hematological cancers specifically, there was a suggestion of an increased risk after immunosuppressive drug exposures, particularly when these were lagged by a period of 5 years (adjusted HR 2.29, 95% CI 1.02–5.15). However, cyclophosphamide seemed to be driving this risk; the adjusted drug-specific HR estimate for cyclophosphamide exposure was 3.55 (95% CI: 0.94–13.37); for azathioprine, 1.02 (95% CI: 0.34–3.03); and for methotrexate, 2.57 (95% CI: 0.80– 8.27). Not that these analyses were adjusted for lupus damage as a surrogate of lupus severity; however, disease activity itself was not assessed in a detailed manner. At the present time, strong statements linking immunosuppressive drug use to cancer risk in SLE may cause unwarranted hesitancy by both patients and physicians to use these agents in SLE. Immunosuppressants can be life-saving, and have demonstrated beneficial effects in terms of control of SLE disease and prevention of other long-term sequelae (such as renal dysfunction). It must be kept in mind also that the cancers that patients with SLE are at highest risk for (compared to the general population) are still rare cancers. For example, Parikh-Patel profiled an increased risk of vulvar/ vaginal cancers, but even among SLE patients, this cancer type will occur only at a rate of approximately one case per 35,000 person years. In contrast, almost all patients with severe SLE will suffer some damage either directly or indirectly related to lupus, if their disease is not well controlled. Thus, as is true for any drug, immunosuppressive exposures in SLE should be evaluated on a case-by-case S. Bernatsky (&) A. E. Clarke Division of Clinical Epidemiology, Research Institute of the McGill University Health Centre (MUHC), 687 Pine Avenue West, V-Building, Montreal, QC, Canada H3A 1A1 e-mail: sasha.bernatsky@mail.mcgill.ca

Rosalind Ramsey-Goldman

Papers

Varying levels of X chromosome coalescence in female somatic cells alters the balance of X-linked dosage compensation and is implicated in female-dominant systemic lupus erythematosus.

Alpha-chlorofatty acid and coronary artery or aorta calcium scores in women with systemic lupus erythematosus. A pilot study

Autoimmune Connective Tissue Disease in Pregnancy

Erratum: The Systemic Lupus International Collaborating Clinics (SLICC) Group-It Was 20 Years Ago Today (Lupus (2011) 20 (1426-1432) DOI: 10.1177/0961203311421501)

Cancer in systemic lupus: what drives the risk?