https://cancerbiologyprogram.med.wayne.edu/pdfs/hallmarks_cancer_article.pdf

Hallmarks of cancer: the next generation.

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

Background Hyperglycemia and insulin resistance are common in critically ill patients, even if they have not previously had diabetes. Whether the normalization of blood glucose levels with insulin therapy improves the prognosis for such patients is not known. Methods We performed a prospective, randomized, controlled study involving adults admitted to our surgical intensive care unit who were receiving mechanical ventilation. On admission, patients were randomly assigned to receive intensive insulin therapy (maintenance of blood glucose at a level between 80 and 110 mg per deciliter) or conventional treatment (infusion of insulin only if the blood glucose level exceeded 215 mg per deciliter and maintenance of glucose at a level between 180 and 200 mg per deciliter). Results At 12 months, with a total of 1548 patients enrolled, intensive insulin therapy reduced mortality during intensive care from 8.0 percent with conventional treatment to 4.6 percent (P<0.04, with adjustment for sequential analyses). The ...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa011300

Intensive Insulin Therapy in Critically Ill Patients

https://www.um.es/biomybiotec/web/Seminarios/2010/papers/Cano_2.pdf

Epithelial-Mesenchymal Transitions in Development and Disease

The origins of the mesenchymal cells participating in tissue repair and pathological processes, notably tissue fibrosis, tumor invasiveness, and metastasis, are poorly understood. However, emerging evidence suggests that epithelial-mesenchymal transitions (EMTs) represent one important source of these cells. As we discuss here, processes similar to the EMTs associated with embryo implantation, embryogenesis, and organ development are appropriated and subverted by chronically inflamed tissues and neoplasias. The identification of the signaling pathways that lead to activation of EMT programs during these disease processes is providing new insights into the plasticity of cellular phenotypes and possible therapeutic interventions.

/pdf/the-basics-of-epithelial-mesenchymal-transition-xe9crzoewf.pdf

The basics of epithelial-mesenchymal transition

Anniversaries are times to look back at the path and provenance of what was achieved and to preview what may lie ahead. As JASN celebrates its 25th anniversary of continuous publication this month, its Editors-in-Chief reflect on these issues and quite warmly thank all of JASN ’s authors, readers

/pdf/jasn-s-silver-jubilee-5ez5tg34y0.pdf

JASN’s Silver Jubilee

Chapter 27 – Treatment of Acute Interstitial Nephritis

Within ten days of immunization with renal tubular antigen (RTA) in adjuvant, all strains of mice develop antitubular basement membrane antibodies (aTBM-Ab) and a L3T4+, I-A restricted, antigen-specific helper/inducer cell.' Six to ten weeks following immunization in disease-susceptible strains, a renal lesion appears that is characterized by tubular atrophy, mononuclear cellular infiltrates, and interstitial fibrosis.' In these susceptible mice, the L3T4+ cell can adoptively transfer disease (disease expression follows cell transfer by 4-6 weeks).2 This L3T4+ cell is not itself an effector cell for delayed-type hypersensitivity (DTH) to RTA, but will induce, in vitro, an Lyt-2+, H-2K restricted, antigen-specific effector cell for DTH to RTA. This Lyt-2' cell will acutely transfer disease (causing severe lesions within five days of having been placed beneath the kidney capsule).' In nonsusceptible strains, a T suppressor cell prevents the emergence of this Lyt-2+ DTH effector cell and may in this way afford protection from disease. We now report the in vivo induction of such suppressor cells in immunized disease-susceptible mice and the subsequent diminution in disease expression. S J L mice, which are disease susceptible, were immunized so as to induce disease. Thereafter, a t various times, they received three weekly injections of RTA-coupled syngeneic spleen cells. Antigen presentation in this context has been demonstrated to induce antigen-specific suppressor cells.4 Controls within each group received cells that had, in the absence of antigen, been subjected to antigen-coupling conditions. After 12 weeks, the mice were sacrificed and bled, and their kidneys were harvested for histologic evaluation. Peripheral node lymphocytes were tested for their ability to suppress a DTH response by transferring them, along with antigen, to the footpads of recipient mice. Footpad swelling 24 hours later has previously been shown to accurately predict nephritogenic potential. The data presented in TABLE 1 indicate that control cells harvested from immunized mice that had received three weekly injections of uncoupled spleen cells contained a DTH effector cell, but no suppressor cell. Cells from mice primed with RTA-coupled cells, when transferred, suppressed the DTH response to RTA. As shown, lymphocyte subset depletion demonstrated that the induced suppressor cell was an Lyt-2+, I-J+, T cell. Depletion of the suppressor cell by aI-Js incubation demonstrated the presence of a functionally suppressed DTH effector cell. Incubation with aLyt-2 etiminated both suppressor and effector cell, thus suggesting that the DTH effector cell was of appropriate phenotype to induce disease. In subsequent experiments, the induced suppressor cell was shown to be antigen-

The Induction of Antigen‐Specific Suppressor Cells (Ts) Diminishes Disease Expression in Mice with Interstitial Nephritis

I NHERITED KIDNEY lesions have historically been classified either by their dominant morphology or by a distinctive functional abnormality. This is because little is really known about their origins or pathophysiology. One consequence of a classification based on morphology is the inevitable tendency to regard diseases with common morphologic features as having shared pathogenic mechanisms, though this mayor may not be true. An enduring example of such a classification system is that of renal cystic diseases. Textbooks on the subject have traditionally grouped together inherited and acquired renal diseases having either macroscopic or microscopic cystS.1.2 Confusion regarding the descriptive nomenclature of cystic diseases is well appreciated, although in the last 10 to 15 years the terminology has become much more consistent. 3 The two most common inherited cystic diseases that typically progress to end-stage are adult polycystic kidney disease (APKD), and the medullary cystic disease-familial juvenile nephronophthisis complex (MCD-FJN). Their patterns of inheritance, natural histories, and associated clinical complications have all been well descibed in recent reports. 4,5 The inheritance of APKD seems to map to the short arm of chromosome 16.6 APKD is typically transmitted with autosomal dominant inheritance, whereas MCDFJN usually follows an autosomal recessive pattern. Together, they account for 10% to 12 % of all end-stage kidney diseases. Although meticulous management of hypertension and infections (especially in APKD) and volume depletion (especially in MCD-FJN) may prevent accelerated loss of renal function, there is no specific therapy for either disease.

PHYSIOLOGY AND CELL BIOLOGY UPDATE Medullary Cystic Disease: An Inherited Form of Autoimmune Interstitial Nephritis?

The mechanisms underlying the linkage of various autoimmune diseases to the major histocompatibility complex remain enigmatic. We have been studying the complex mechanism of susceptibility to experimental interstitial nephritis in mice. Following immunization with heterologous renal tubular antigens in complete Freund’s adjuvant, susceptible mice develop antitubular basement membrane (anti-TBM) antibodies and interstitial T-cell infiltrates with eventual interstitial fibrosis and progressive renal insufficiency.’ Susceptibility to murine anti-TBM disease is genetically dominant and maps to the class I locus H-2KS*d. Susceptible and nonsusceptible strains mount similar anti-TBM antibody responses to the renal tubular antigen (RTA) but are distinctly different in their effector T-cell responses. In previous work we showed that both susceptible and nonsusceptible mice initially differentiate two different effector T cells after immunization with RTA: L3T4+, I-A restricted T cells, and Lyt-2+, H-2K restricted T cells.’ In vivo studies have shown that in susceptible mice only the Lyt-2+ cells persist, whereas in nonsusceptible mice only the L3T4+ cells remain.* This is an important distinction, because although both phenotypes mediate delayed-type hypersensitivity (DTH) to RTA, only the Lyt-2’ T cells typically transfer interstitial nephritis. This selection of effector T-cell phenotype can be duplicated in vitro and was previously shown to be regulated by antigen-primed, Lyt-2+, I-J+ regulatory T cells.3 Previous studies showed that contrasuppressor T cells can play a critical role in the expression of organ-specific a~to immuni ty .~ Therefore, we examined the relative roles of suppressor (Ts) and contrasuppressor (Tcs) cells in regulating the selection of effector T-cell phenotype, because such selection correlates strongly with susceptibility to disease. These studies were .performed using a previously described method for in vivo induction of antigen-specific effector T cells from a naive spleen cell p ~ p u l a t i o n . ~ In brief, naive syngeneic spleen cells are cocultured with soluble RTA, growth factors including interleukin-2 (IL-2), and supernatants from syngeneic helper T-cell lines for 5 days a t 37OC. T-cell subpopulations are then negatively selected with anti-L3T4 or anti-Lyt-2 antibodies and complement, and the ability of the remaining cells to mediate DTH is assessed by local adoptive transfer in the presence of antigen. Under such conditions, the phenotype of the day 5 effector T cell is Lyt-2+ in SJL and [SJL x BIO.S(8R)]F, mice (both susceptible) and L3T4+ in BIO.S(8R) (nonsusceptible) mice. If Vicia villosa lectin-adherent Tcs cells are removed before culture, the phenotype of the effector T cell is L3T4’ in all three strains. If the remaining lectin nonadherent cells are further depleted with anti-I-J’, effector T cells of both phenotypes differentiate and persist in all three strains, a finding consistent with the presence of a lectin nonadherent Ts that suppresses Lyt-2+ cells. Further studies have shown that the function of the lectin-adherent Tcs cell (which is an Lyt-2+, I-J+, T cell) can be replaced by a soluble factor from those cells. This factor is antigen binding,

Eric G. Neilson

Papers

JASN’s Silver Jubilee

Chapter 27 – Treatment of Acute Interstitial Nephritis

The Induction of Antigen‐Specific Suppressor Cells (Ts) Diminishes Disease Expression in Mice with Interstitial Nephritis

PHYSIOLOGY AND CELL BIOLOGY UPDATE Medullary Cystic Disease: An Inherited Form of Autoimmune Interstitial Nephritis?

Contrasuppression As a Determinant of Susceptibility to Autoimmune Injury