Mechanism of immunosuppression following hemorrhage: defective antigen presentation by macrophages

The mechanism by which simple hemorrhage profoundly impairs the proliferative response of T lymphocytes to mitogen and alloantigen, produces a defect in interleukin-2 generation, and increases the susceptibility to sepsis remains unknown. Since antigen presentation (AP) by the macrophage (M phi) plays a critical role in the antigen-specific activation of T-helper cells and lymphokine production, we investigated whether the function of the M phi as an AP cell is altered following hemorrhage. C3H/HEJ mice were bled to a mean BP of 35 mm Hg, maintained at that level for 1 hr, and then resuscitated. There was no mortality with this model. Control mice were not bled but otherwise treated identically. Immediately after resuscitation the mice were sacrificed and peritoneal M phi (PM phi) as well as splenic adherent cells (SAC) were harvested. AP function was tested by coculturing different numbers of PM phi and SAC with D10.G4.1 cells (2 x 10(4) cells/well) in the presence of conalbumin (300 micrograms/ml). This T-helper cell clone proliferates upon recognition of conalbumin in the context of Iak (a M phi surface membrane glycoprotein), thus directly reflecting M phi AP capability. After 72 hr of incubation, the cultures were pulsed with [3H]thymidine and harvested. D10.G4.1 proliferations induced via AP by PM phi and SAC from hemorrhaged-resuscitated mice were 29 and 24% of control, respectively (P less than 0.05). Thus, we conclude that AP by M phi following hemorrhage is defective despite adequate resuscitation, a mechanism which could explain the state of immunosuppression and enhanced susceptibility to sepsis.     

Energetics of defective macrophage antigen presentation after hemorrhage as determined by ultraresolution 31P nuclear magnetic resonance spectrometry: restoration with adenosine triphosphate-MgCl2.

BACKGROUND. The purpose of this study was to determine whether a decrease in macrophage energetics contributes to the profound immune dysfunction that occurs after hemorrhage and, if so, whether adenosine triphosphate (ATP)-MgCl2 treatment has any beneficial effects on the above parameters. METHODS. C3H/HeN mice were bled to a mean blood pressure of 35 mm Hg, maintained at that pressure for 60 minutes, resuscitated with their own shed blood and Ringer's lactate, and treated with ATP-MgCl2 (80 mumol/kg body weight) or saline solution (vehicle). Peritoneal macrophages were harvested 1 hour after resuscitation and ATP levels were determined by 31P nuclear magnetic resonance spectrometry. In addition, macrophage functions were determined by measuring antigen presentation capacity (AP), as well as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF) synthesis. RESULTS. Hemorrhage caused a significant decrease in peritoneal macrophage AP function, as well as IL-1, IL-6, and TNF synthesis, by 52% +/- 14%, 91% +/- 12%, 78% +/- 8%, and 89% +/- 8%, respectively, which was correlated with a 78% +/- 6% decrease in macrophage ATP levels (p less than 0.05). Treatment with ATP-MgCl2 after hemorrhage restored macrophage ATP levels (p less than 0.05) and significantly increased (p less than 0.05) macrophage AP, IL-1, IL-6, and TNF release by 110% +/- 21%, 130% +/- 38%, 124% +/- 17%, and 66% +/- 24%, respectively. CONCLUSIONS. The decreased macrophage ATP levels may be the cause of defective macrophage AP and cytokine release after hemorrhage, and both macrophage ATP levels and macrophage immune functions can be restored with adjuvant ATP-MgCl2 treatment after hemorrhage.     

Cortisol secretion after hemorrhage: multiple mechanisms.

Multiple mechanisms appear to be involved in mediation of increased secretion of cortisol after hemorrhage. Signals from cardiovascular receptors are transmitted to the hypothalamus through ascending neural pathways to release ACTH. Angiotensin II stimulates release of ACTH by an action on the median eminence, but does not stimulate adrenal secretion of cortisol directly. However, secretion of cortisol can increase rapidly after hemorrhage without changes in ACTH. Common afferent pathways probably mediate all these mechanisms.     

The T-cell anergy induced by Leishmania amazonensis antigens is related with defective antigen presentation and apoptosis

Leishmania amazonensis is the main agent of diffuse cutaneous leishmaniasis, a disease associated with anergic immune responses. In this study we show that the crude antigen of Leishmania amazonensis (LaAg) but not L. braziliensis promastigotes (LbAg) contains substances that suppress mitogenic and spontaneous proliferative responses of T cells. The suppressive substances in LaAg are thermoresistant (100 degrees C/1h) and partially dependent on protease activity. T cell anergy was not due to a decreased production of growth factors as it was not reverted by addition of exogenous IL-2, IL-4, IFN-gamma or IL-12. LaAg did not inhibit anti-CD3-induced T cell activation, suggesting that anergy was due to a defect in antigen presentation. It was also not due to cell necrosis, but was accompanied by expressive DNA fragmentation in lymph node cells, indicative of apoptosis. Although pre-incubation of macrophages with LaAg prevented their capacity to present antigens, this effect was not due to apoptosis of the former. These results suggest that the T cell anergy found in diffuse leishmaniasis may be the result of parasite antigen-driven apoptosis of those cells following defective antigen presentation.     

Immunoprotective effect of a calcium channel blocker on macrophage antigen presentation function, major histocompatability class II antigen expression, and interleukin-1 synthesis after hemorrhage

Hemorrhage induces a severe suppression of the immune system resulting in increased susceptibility to sepsis. Although studies indicate beneficial effects of calcium channel blockers on cell and organ functions after low-flow conditions, it remains unknown whether such agents have any effects on different immune responses after hemorrhage. To study this, C3H/HeN mice were bled to a mean blood pressure of 35 mm Hg and were maintained for 60 minutes, followed by resuscitation with their own shed blood and adequate fluid. The mice received either the water-soluble calcium channel blocker diltiazem (400 or 2400 micrograms/kg body weight) or saline solution (vehicle). Peritoneal macrophages were obtained by lavage 24 hours later. Antigen presentation was measured by coculturing peritoneal macrophages with the D10.G4.1 helper T-lymphocyte clone. Immune associated antigen (Ia) expression was determined by direct immunofluorescence. Interleukin (IL)-1, 6, and tumor necrosis factor-alpha (TNF) levels in peritoneal macrophage supernatants were measured by use of cytokine-specific cellular assays. Hemorrhage caused a significant decrease in peritoneal macrophage antigen presentation function, Ia expression, and IL-1 and IL-6 synthesis in the vehicle-treated group, whereas TNF levels were increased. However, both doses of diltiazem significantly improved peritoneal macrophage antigen presentation, Ia expression, and IL-1 synthesis. IL-6 synthesis was only increased with high doses of diltiazem, whereas both diltiazem doses decreased TNF production. These results indicate that the calcium channel blocker diltiazem can markedly improve macrophage functions after hemorrhage. The use of diltiazem might offer a new therapeutic modality in the treatment of immunosuppression and in decreasing the susceptibility to sepsis after hemorrhagic shock.     

Depressed antigen presentation function and membrane interleukin-1 activity of peritoneal macrophages after laparotomy

Although major tissue trauma produces profound depression of cell-mediated immunity, it is not known whether surgical trauma (i.e., midline laparotomy) has any adverse effect on the antigen presentation function and membrane interleukin-1 (IL-1) activity of peritoneal macrophages. To study this, C3H/HEJ (endotoxin-tolerant) mice were anesthetized. An approximately 1-inch midline abdominal incision was made, followed by abdominal closure. On days 1, 3, 5, and 7, peritoneal macrophages were harvested by means of peritoneal lavage, and antigen presentation capability was tested by incubating various numbers of peritoneal macrophages with 2 X 10(4) D10.G4.1 cells per well in the presence of conalbumin (400 micrograms/ml). The T helper cell clone (D.10.G4.1) proliferates on recognition of conalbumin in the context of Iak and also proliferates in the presence of membrane-bound IL-1 plus concanavalin A. To measure membrane IL-1 expression in peritoneal macrophages, Concanavalin A (10 micrograms/ml) was substituted for conalbumin. Cultures were incubated for 72 hours, pulsed with tritiated thymidine, and harvested. Peritoneal macrophages from laparotomized mice induced significantly less T helper cell proliferation on days 1 and 3 in the antigen presentation assay (37% and 30%, respectively; p less than 0.05) and in the membrane IL-1 assay (14% and 10%, respectively; p less than 0.05) as compared with the control. This difference was not detectable on day 5. More effective antigen presentation capability (167% of control; p less than 0.05) was seen on day 7. Thus laparotomy by itself produces marked depression of both antigen presentation function and membrane IL-1 activity of peritoneal macrophages, which may enhance susceptibility to intra-abdominal sepsis.     

Acute presentation of thymoma with infarction or hemorrhage

The presentation of thymomas is variable; most are asymptomatic and others present with local compression symptoms or a parathymic syndrome. Rarely thymomas present as an acute emergency with severe chest pain from either infarction or hemorrhage of the tumor. This rare presentation usually leads the clinician initially away from the diagnosis of thymoma. We present 4 patients who presented with infarction (3 patients) and hemorrhage (1 patient) who were initially believed to have a lymphoma. Preoperative biopsies were unrevealing. All had a complete resection and were in the early Masaoka stage. There have been no recurrences in follow-up. The astute clinician should be aware of this unusual presentation. The prognosis seems to be good in patients who present with infarction or hemorrhage.     

Unique presentation and management of Gowers intrasyringal hemorrhage

Context: Intrasyringal hemorrhage was first described in literature in the renowned Lectures on Diseases of the Nervous System by Sir William Richard Gowers [Gowers W. A lecture on syringal haemorrhage into the spinal cord. Lancet [Internet]; 162(4180):993–997. [cited 2019 August 19]. Available from https://www.sciencedirect.com/science/article/pii/S0140673601362785]. The pathophysiology of this disease is a hemorrhage within a preexisting intramedullary fluid-filled cavity or hydrosyringomyelia in the spinal cord. Most common symptoms of this disease are numbness, weakness, paresthesia in the extremities and gait disturbances. Since first noted in 1903, there have been just fourteen confirmed cases of this disease reported in literature, making it extremely rare and difficult to study.Findings: Here we discuss a unique presentation of Gowers intrasyringal hemorrhage. The patient is a male in his late teens with no prior established neurological history. He presented at our institution four days post suspected injury with persistent mild left upper extremity numbness and weakness. The patient was admitted and underwent an MRI of the cervical spine without intravenous contrast. The imaging findings confirm subacute on chronic Gowers intrasyringal hemorrhage in the setting of a Chiari 1 malformation. This patient underwent neurosurgical intervention four months post initial presentation and had complete postoperative resolution of his interval non-progressive but persistent symptoms.Clinical relevance: This unique case suggests immediate surgical intervention may not always be necessary for treating Gowers intrasyringal hemorrhage.     

Trichomonas vaginalis infection and prostate-specific antigen concentration: Insights into prostate involvement and prostate disease risk

Background: The protist Trichomonas vaginalis causes a common, sexually transmitted infection and has been proposed to contribute to the development of chronic prostate conditions, including benign prostatic hyperplasia and prostate cancer. However, few studies have investigated the extent to which it involves the prostate in the current antimicrobial era. We addressed this question by investigating the relation between T. vaginalis antibody serostatus and serum prostate-specific antigen (PSA) concentration, a marker of prostate infection, inflammation, and/or cell damage, in young, male, US military members. Methods: We measured T. vaginalis serum IgG antibodies and serum total PSA concentration in a random sample of 732 young, male US active duty military members. Associations between T. vaginalis serostatus and PSA were investigated by linear regression. Results: Of the 732 participants, 341 (46.6%) had a low T. vaginalis seropositive score and 198 (27.0%) had a high score, with the remainder seronegative. No significant differences were observed in the distribution of PSA by T. vaginalis serostatus. However, slightly greater, nonsignificant differences were observed when men with high T. vaginalis seropositive scores were compared with seronegative men, and when higher PSA concentrations were examined (≥0.70 ng/mL). Specifically, 42.5% of men with high seropositive scores had a PSA concentration greater than or equal to 0.70 ng/mL compared with 33.2% of seronegative men (adjusted P = .125). Conclusions: Overall, our findings do not provide strong support for prostate involvement during T. vaginalis infection, although our suggestive positive findings for higher PSA concentrations do not rule out this possibility entirely. These suggestive findings may be relevant for prostate condition development because higher early- to mid-life PSA concentrations have been found to predict greater prostate cancer risk later in life.     

增强抗原呈递功能的树突状细胞疫苗

树突状细胞（DC）疫苗的研究已成为当前肿瘤免疫治疗的一大热点。随着对DC的不断认识,其强大的功能可塑性为发展增强其抗原呈递功能的DC疫苗提供了新思路,现就DC疫苗增强其抗原呈递功能的种种途径进行综述。     

Lack of T cell proliferation without induction of nonresponsiveness after antigen presentation by endothelial cells.

BACKGROUND: After priming or reactivation in lymph nodes, T cells recirculate to sites of inflammation, and enter tissues by migrating across activated endothelium. Given that activated endothelial and tissue parenchymal cells express both class I and class II MHC molecules, it is probable that transmigrating T cells encounter cognate antigen on endothelial cells, and on tissue parenchymal cells once they have entered the tissue. METHODS: In this study the consequences of antigen presentation by endothelial and epithelial cells to human CD4+ T cell clones were analyzed and compared by a two-step culture system. RESULTS: T cell clones that required B7-mediated costimulation to be activated were found not to be able to proliferate to antigen presented by either endothelial or epithelial cells, unless trans-costimulation was provided by the addition of B7-transfected cells in the cultures. Furthermore, antigen presentation by epithelial cells induced nonresponsiveness in the T cell clones. In contrast, after cognate recognition on endothelial cells, the ability of the T cell clones to proliferate to a subsequent rechallenge with antigen presented on a specialized APC was unaffected. CONCLUSIONS: These data suggest that endothelial cells have unique properties as antigen-presenting cells, in that they do not influence the subsequent reactivity of cognate T cells.     

Insights into causes of sexual ambiguity

Our understanding of the causes of sexual ambiguity has progressed from the determination of the hormonal etiologies to defining the genetic basis of intersex disorders. The localization of specific genes involved in the process of sexual differentiation has made it possible to determine the mutations and other molecular events that result in sexual ambiguity. With this information, some disorders can now be diagnosed before birth and possibly even treated in utero.     

Spontaneous retroperitoneal hemorrhage: unusual presentation of renal cancer

Spontaneous retroperitoneal hemorrhage as the presenting sign of renal cancer is rare. A case of spontaneous retroperitoneal hemorrhage from a renal carcinoma is described and management possibilities presented. While it is true that renal angiomyolipomas are the main cause of spontaneous retroperitoneal renal bleeding, the possibility of renal cancer should be entertained more often in the differential diagnosis.     

New Insights into the Pathomechanism of Postintubation Arytenoid Subluxation

Background: Impaired movement of the cricoarytenoid joint with hoarseness and immobility of the vocal ligament can occur as a consequence of endotracheal intubation. The biomechanics and pathomechanism of cricoarytenoid subluxation have not been demonstrated to date.

Methods: The present study attempts to simulate the trauma that has been associated with arytenoid cartilage subluxation in intubation trials on 37 unfixed larynges in cadavers from persons aged 25 to 89 years. Larynges were intubated or extubated according to former conceptions of arytenoid subluxation, which assume that the arytenoid tip enters the lumen of the tracheal tube, or that a deflection of the arytenoid occurs during withdrawal of the endotracheal tube with the cuff of the tube only partially deflated. Also, manual attempts were carried out to subluxate the arytenoid cartilage. Subsequently after dissecting the left and right cricoarytenoid joint from each larynx, the morphologic changes induced experimentally were analyzed using gross microscopic and histologic methods.

Results: Within the scope of the experiment, it proved impossible to produce any subluxation of a cricoarytenoid joint. Histologic analysis revealed injuries of synovial folds, joint-surface impressions of the articular cartilage, and fractures in the area of the subchondral bone in some joints.