Splenic White Pulp Research Articles

The effect of Toll-like receptor stimulation on the motility of regulatory T cells

Regulatory T cells (Tregs) have suppressive functions and play an important role in controlling inflammation and autoimmunity. The migratory capacity of Tregs determines their location and their location determines whether they inhibit the priming of naïve lymphocytes in lymphoid tissues or the effector phase of immune responses at inflamed sites. Tregs generated or expanded in vitro are currently being tested in clinics for the treatment of autoimmune disorders, however, little is known about the factors controlling their migration towards therapeutically relevant locations. In this study, we have modulated Treg dynamics using Toll-like receptor (TLR) agonists. Dynamic imaging with confocal and two-photon microscopy revealed that Tregs generated in vitro and stimulated with P3C (a TLR2 agonist) but not with R848 (a TLR7 agonist) or LPS (a TLR4 agonist) showed enhanced cell migration within splenic white pulp or draining lymph node when transferred into mice intravenously or into the footpad, respectively. In summary, our data demonstrate that Tregs are more motile in response to direct TLR stimulation in particular towards TLR2 signals. This may have implications for efficient clinical Treg induction protocols.

The emerging spectrum of cardiopulmonary pathology of the coronavirus disease 2019 (COVID-19): Report of 3 autopsies from Houston, Texas, and review of autopsy findings from other United States cities

This paper collates the pathological findings from initial published autopsy reports on 23 patients with coronavirus disease 2019 (COVID-19) from 5 centers in the United States of America, including 3 cases from Houston, Texas. Findings confirm that COVID-19 is a systemic disease with major involvement of the lungs and heart. Acute COVID-19 pneumonia has features of a distinctive acute interstitial pneumonia with a diffuse alveolar damage component, coupled with microvascular involvement with intra- and extravascular fibrin deposition and intravascular trapping of neutrophils, and, frequently, with formation of microthombi in arterioles. Major pulmonary thromboemboli with pulmonary infarcts and/or hemorrhage occurred in 5 of the 23 patients. Two of the Houston cases had interstitial pneumonia with diffuse alveolar damage pattern. One of the Houston cases had multiple bilateral segmental pulmonary thromboemboli with infarcts and hemorrhages coupled with, in nonhemorrhagic areas, a distinctive interstitial lymphocytic pneumonitis with intra-alveolar fibrin deposits and no hyaline membranes, possibly representing a transition form to acute fibrinous and organizing pneumonia. Multifocal acute injury of cardiac myocytes was frequently observed. Lymphocytic myocarditis was reported in 1 case. In addition to major pulmonary pathology, the 3 Houston cases had evidence of lymphocytic pericarditis, multifocal acute injury of cardiomyocytes without inflammatory cellular infiltrates, depletion of splenic white pulp, focal hepatocellular degeneration and rare glomerular capillary thrombosis. Each had evidence of chronic cardiac disease: hypertensive left ventricular hypertrophy (420 g heart), dilated cardiomyopathy (1070 g heart), and hypertrophic cardiomyopathy (670 g heart). All 3 subjects were obese (BMIs of 33.8, 51.65, and 35.2 Kg/m2). Overall, the autopsy findings support the concept that the pathogenesis of severe COVID-19 disease involves direct viral-induced injury of multiple organs, including heart and lungs, coupled with the consequences of a procoagulant state with coagulopathy.

Phenotypical Characterization of Spleen Remodeling in Murine Experimental Visceral Leishmaniasis.

Background: Visceral leishmaniasis (VL) is caused by Leishmania infantum or L. donovani infection. One of the main problems related to this disease is the emergence of severe clinical forms with a lethality of 5–20%, even while under specific treatment. In humans and other species susceptible to fatal VL, such as dogs and hamsters, the disruption of splenic white pulp (WP) is accompanied by disease progression. Control of VL progression is seen in BALB/c mice, as evidenced by a mild clinical presentation and controlled parasite replication in the liver and spleen. In this study, we investigated the features involved in the morphological remodeling of splenic compartments associated with the control of VL progression to death.Methods: We evaluated cohorts of BALB/c mice after 30, 60, and 90 days of infection by L. infantum. Spleen morphology, cell population subsets and cytokine production were studied in the spleen using flow- and histo-cytometry.Results: Intraperitoneal infection with 108 promastigotes of L. infantum led to progressive increases in spleen size at 60 and 90 days after infection. Splenomegaly was the only clinical sign of disease observed. At 30 days after infection, hyperplasia in the WP and decreased numbers of plasmacytoid dendritic cells were observed. The WP hyperplasia subsided at 60 days post-infection. However, the splenomegaly remained in association with increased numbers of macrophages, B and T lymphocytes and plasma cells. An increased number of lymphoid tissue inducer (LTi) cells was observed; these were distributed around the periarteriolar lymphoid sheath in control mice and scattered throughout the red pulp in the Leishmania-infected mice. After 90 days of infection, increased IL-6 and IFN-γ production was seen in the spleen, as well as higher frequencies of follicular and plasmacytoid dendritic cells.Conclusion: The data presented herein emphasizes the potential role of spleen remodeling in the control of severe forms of VL and highlights features potentially involved in this process.

CD8 T-cell Recruitment Into the Central Nervous System of Cuprizone-Fed Mice: Relevance to Modeling the Etiology of Multiple Sclerosis

Cuprizone (CPZ)-feeding in mice induces atrophy of peripheral immune organs (thymus and spleen) and suppresses T-cell levels, thereby limiting its use as a model for studying the effects of the immune system in demyelinating diseases such as Multiple Sclerosis (MS). To investigate whether castration (Cx) can protect the peripheral immune organs from CPZ-induced atrophy and enable T-cell recruitment into the central nervous system (CNS) following a breach of the blood-brain barrier (BBB), three related studies were carried out. In Study 1, Cx prevented the dose-dependent reductions (0.1% < 0.2% CPZ) in thymic and splenic weight, size of the thymic medulla and splenic white pulp, and CD4 and CD8 (CD4/8) levels remained comparable to gonadally intact (Gi) control males. Importantly, 0.1% and 0.2% CPZ were equipotent at inducing central demyelination and glial activation. In Study 2, combining Cx with 0.1% CPZ-feeding and BBB disruption with pertussis toxin (PT) enhanced CD8+ T-cell recruitment into the CNS. The increased CD8+ T-cell level observed in the parenchyma of the cerebrum, cerebellum, brainstem and spinal cord were confirmed by flow cytometry and western blot analyses of CNS tissue. In Study 3, PT+0.1% CPZ-feeding to Gi female mice resulted in similar effects on the peripheral immune organs, CNS demyelination, and gliosis comparable to Gi males, indicating that testosterone levels alone were not responsible for the immune response seen in Study 2. The combination of Cx+0.1% CPZ-feeding+PT indicates that CPZ-induced demyelination can trigger an “inside-out” immune response when the peripheral immune system is spared and may provide a better model to study the initiating events in demyelinating conditions such as MS.

Histochemical Studies on the Major Lymphoid Organs in Various Chicken Genotypes

A total number of eighteen day old Hansli chicks and eighteen day old Vencobb broiler chicks were divided into three age groups viz. group I (up to 1 month), group II (1-3 months) and group III (3-6 months) with six birds in each age group. On each observation day (4th week, 12th week and 24th week), six birds from each breed were used for the study of histochemical features of the thymus, spleen and bursa of Fabricius. It was found that the capsule, septa and tunics of blood vessels revealed age specific PAS activities, whereas the Alcian blue activities varied with age and was restricted to the thymic capsule and trabeculae. The splenic capsule, tunics of blood vessels and intercellular region of splenic white pulp revealed age specific PAS positive activity, whereas the Alcian blue activity was only reported in the splenic capsule of 12th week age Hansli chicken and Vencobb broiler chicken. The apical borders of both follicle associated epithelium and interfollicular epithelium, sub-epithelial region, cortico-medullary junction, medulla of lymphoid follicle, interfollicular connective tissue, central connective tissue core of bursal plicae, walls of blood vessels, tunica muscularis and tunica serosa revealed age specific PAS activities, whereas the apical borders of follicle associated epithelium (FAE), interfollicular epithelium (IFE) and goblet cells of lining surface epithelium, tunica muscularis and tunica serosa showed age specific Alcian blue activities in both the birds.

Evaluation of the splenic injury following exposure of mice to bisphenol S: A mass spectrometry-based lipidomics and imaging analysis

BackgroundThe widespread use of bisphenol A (BPA) substitutes has aroused great attention towards their toxicological evaluation in vivo and in vitro. Considering the intimate correlation between BPA and metabolic diseases, we explored whether bisphenol S (BPS), a major substitute to BPA, could cause the splenic toxicity by disturbing the lipid metabolism in mouse model. MethodsWe investigated the splenic injury by combing the mass spectrometry (MS)-based lipidomics and imaging analysis, as well as molecular biological methods. Mice were divided into three groups (control-olive oil, 10 and 100 μg-BPS/kg body weight/day group) and treated by BPS in 56 days. ResultsTwo of BPS-treated concentrations induced the splenic morphological alterations and inflammation, including the decreased numbers and cellularity in the periarteriolar lymphoid sheath (T cell zone) and paucicellular primary lymphoid follicles (B cell zone) in splenic white pulp. Lipidome profiling of spleen after BPS treatment was also changed with up-regulated sphingosine [So], neutral glycosphingolipids [CerG], cholesteryl ester [ChE], diacylglycerols [DAG], lysophosphatidylcholine [LPC], lysophosphatidylethanolamine [LPE], phosphatidylglycerols [PG], phosphatidylinositols [PI] and phosphatidylserine [PS] as well as down-regulated ceramide [Cer], phosphatidylethanolamines [PE] and sphingomyelin [SM] compared to the control group. More importantly, significant different lipids in abundance and spatial distribution also implicated that white pulp were more sensitive to BPS treatment than other splenic sub-structures. Signaling lipids such as So (d18:0), Cer (d18:1/24:0), Cer (d18:1/22:0), SM (d18:1/22:1) and SM (d18:1/24:2) associated with inflammation were remarkable changed and co-localized in the splenic white pulp. ConclusionsOur finding indicated that BPS exposure promoted the splenomegaly, pro-inflammatory activation and morphological alterations, as well as induced the lipidome perturbation in the immune cells of white pulp, which might be expected to contribute a new perspective of bisphenol-induced organ injury.

288 Se deficiency aggravates AFB1-induced immunotoxicity in chick spleen via regulating six selenoprotein and redox/inflammation/apoptotic signaling

Abstract This study was designed to reveal the underlying mechanism of Se-mediated protection against aflatoxin B1 (AFB1)-induced splenic injury in broilers. Four groups of day-old Cobb male broilers (n = 5 cages/diet, 6 chicks/cage) were arranged in a 3-wk 2×2 factorial design trial that fed a Se-deficient, corn and soy–based diet (BD, 36 μg Se/kg) or the BD + 1.0 mg AFB1/kg, 0.3 mg Se/kg, or 1.0 mg AFB1/kg with 0.3 mg Se/kg (as 2-hydroxy-4-methylselenobutanoic acid). Serum and spleen were collected at wk 3 to assay for histology, cytokines, redox status, and selected inflammation- and apoptosis-related genes and proteins, and selenogenome. Dietary AFB1 induced the growth retardation and spleen injury, decreasing (P &amp;lt; 0.05) body weight gain, feed intake, feed conversion efficiency, and serum interleukin-1β, increasing (P &amp;lt; 0.05) spleen index and serum interleukin-6, and reduced the splenic lymphocyte number and white pulp region and histiocyte proliferation in Se adequate groups. However, Se deficiency aggravated (P &amp;lt; 0.05) these AFB1-induced changes. Moreover, Se deficiency decreased (P &amp;lt; 0.05) splenic glutathione peroxidases (GPX) activities and glutathione concentration in AFB1 exposed groups. Furthermore, Se deficiency also upregulated (P &amp;lt; 0.05) the antimicrobial (beta defensin 1 and 2) and apoptotic (Caspase 3 and Caspase 9) genes but downregulated (P &amp;lt; 0.05) antiapoptotic (B-cell lymphoma 2) and inflammatory (E3 ubiquitin-protein ligase CBL-B) genes at mRNA and(or) protein levels in AFB1 supplementation groups. Additionally, Se deficiency downregulated (P &amp;lt; 0.05) GPX3, thioredoxin reductase 1 (TXNRD 1), GPX4 and selenoprotein (SELENO) S and upregulated (P &amp;lt; 0.05) SELENOT and SELENOU in spleen in AFB1 administered groups. In conclusions, dietary Se deficiency aggravated AFB1-induced spleen injury in chicks, partially through the regulation of the oxidative stress, inflammatory and apoptotic signaling and six selenoproteins (Supported in part by Chinese Natural Science Foundation Projects 31772636 and 31501987).

Pro-Cellular Exhaustion Markers are Associated with Splenic Microarchitecture Disorganization and Parasite Load in Dogs with Visceral Leishmaniasis

In canine visceral leishmaniasis (CVL), splenic white pulp (SWP) disorganization has been associated with disease progression, reduced cytokine and chemokine expression and failure to control the parasite load. This profile is compatible with the cellular exhaustion previously shown in human visceral leishmaniasis. The present study aimed to evaluate the in situ expression of cellular exhaustion markers and their relation to clinical signs, SWP disorganization and parasite load. Forty dogs naturally infected by Leishmania infantum were grouped according to levels of SWP organization and parasite load. SWP disorganization was associated with reductions in the periarteriolar lymphatic sheath and lymphoid follicles/mm2 and worsening of the disease. Apoptotic cells expressing CTLA-4+ increased in dogs with disorganized SWP and a high parasite load. In the same group, PD-L1 and LAG-3 gene expression were reduced. A higher number of CD21+TIM-3+ B cells was detected in disorganized spleens than in organized spleens. Apoptosis is involved in periarteriolar lymphatic sheath reduction and lymphoid follicle atrophy and is associated with CTLA-4+ cell reductions in the splenic tissue of dogs with visceral leishmaniasis (VL). Failure to control the parasite load was observed, suggesting that cell exhaustion followed by T and B cell apoptosis plays a role in the immunosuppression observed in CVL.

Terminologia Histologica 10 years on: some disputable terms in need of discussion and recent developments

At first sight, the issue of morphological terminology may seem to be a “closed and unchanging chapter”, as many of the structures within the human body have been known for decades or even centuries. However, the exact opposite is true. The initial knowledge of the microscopic structure of the human body has been continuously broadening thanks to the development of new specialized staining techniques, discovery of the electron microscope, or later application of histochemical and immunohistochemical methods into routine tissue examination. Contrary to popular belief, histology has a status of constantly developing scientific discipline, with continuous influx of new knowledge, resulting in an unavoidable necessity to revise the histological nomenclature at regular intervals. The team of experts of the Federative International Programme on Anatomical Terminology, a working group of the International Federation of Associations of Anatomists, published in 2008 the First Edition of Terminologia Histologica. Terminologia Histologica (TH) is the best and most extensive of all the histological nomenclatures ever issued. However, here we suggest that several terms of important histological structures are still missing while several other terms are disputable. First, we present some clinically important terms of cells and tissue structures for inclusion in the next TH and, in a second part, we refer to some new terms in the current edition of the TH which are not yet mentioned in current histology textbooks (e.g., fusocellular connective tissue, bundle bone as the third type of bone tissue, spongy layer of vagina or arteria vaginata from the splenic white pulp). With this article we hope to start a wide scientific discussion which will lead to an inambiguous definition and demonstration of typical examples of all terms in the TH, with the result that the new edition of the Terminologia Histologica will become an internationally accepted communication tool for all practitioners and teachers of histology alike.

A Combination of Muramylpeptides from Gram-Negative Bacteria Corrects Hematological and Immunological Disorders Induced by Cyclophosphamide.

We have studied the effect of a combination of three natural muramylpeptides containing a meso-diaminopimelic acid residue (polyramyl) on the subpopulations of circulating T cells, spleen morphology, and leukocyte level in the blood of C57Bl/6 mice with cyclophosphamideinduced immunosuppression. Intraperitoneal injections of cyclophosphamide in a dose of 100 mg/kg on days 1, 3, 5, and 7 of the experiment reduced leukocyte count and the relative number of CD4+ T cells in the blood, and also depleted the cellular composition of splenic white pulp on day 10. Subcutaneous injections of polyramyl in a dose of 200 μg/mouse on days 8 and 9 practically completely restored blood leukocytes count and morphology of the splenic white pulp. Moreover, administration of polyramyl induced marked tendency to increase in the relative number of CD4+ T cells and CD4/CD8 ratio in mice with cyclophosphamideinduced immunosuppression.

Clinical manifestations following intramuscular exposure of mice to a lethal dose of ricin

Abstract Ricin a plant toxin derived from seeds of Ricinus communis, irreversibly inactivates ribosomes by site-specific depurination, thereby arresting cell protein synthesis, while its clinical manifestations following intramuscular exposure have not yet been investigated in depth. Here we report an extensive pathological study of intramuscular intoxication with a lethal dose of ricin in a murine model. Ricin injection caused neutrophilia, thrombocytopenia and coagulopathy. Although histopathological alternations including hemorrhages, vessel congestion and focal necrosis were observed in various organs, major insults were limited to the spleen, bone marrow (BM) and cardiovascular system. Intensive atrophy, evident in the BM and splenic white pulps, were accompanied be severe depletion of megakaryocytes in both organs. Moreover, splenic T and B lymphocytes, NK cells, macrophages and dendritic cells decreased significantly. The most striking damage was in the heart, where we observed diffuse hemorrhages, myocyte disconnection, loss of striation, interstitial edema, collagen deposition and elevated levels of serum cardiac troponin. Finally, echocardiography revealed marked thickening of the walls, along with sequential decrease in left ventricular volume. These were accompanied by a significant reduction in stroke volume and cardiac output, while the ejection fraction remained unaltered. Measurements of the toxin direct catalytic performance in the spleen, BM and heart of the ricin-intoxicated mice revealed no substantial 28S rRNA depurination. The lack of measurable ricin catalytic activity in conjunction with the striking clinical disorders observed, suggests that ricin affects these organs in an indirect manner.

LAG-3 modulation of natural killer cell immunoregulatory function

Abstract Natural killer (NK) cells suppress antiviral immunity by killing a fraction of virus-specific CD4 T cells. This occurs during the first 3 days of infection, is perforin-dependent, and coincides with NK-cell localization in the splenic white pulp. While the receptors governing this NK-cell activity are ill-defined, it is clear that negative feedback mechanisms must exist to prevent excessive pruning of T-cell responses. Comparative transcriptome analysis of red pulp and white pulp localized NK-cells derived from late in the window of immunoregulatory activity (day 3) reveals increased expression of Lag3 in white pulp NK-cells. LAG-3 is an inhibitory receptor that binds peptide-bound major histocompatibility complex II (pMHC-II). We find a progressive increase in LAG-3 protein expression on NK-cells with time post-infection and localization to the white pulp. Consistent with its putative inhibitory role, antibody-mediated neutralization of LAG-3 enhances NK-cell killing capacity in vitro. Preliminary analysis reveals reduced virus-specific T cells in mice lacking Lag3 in NK-cells (Ncr1Cre+Lag3fl/fl) relative to control mice. We hypothesize that LAG-3 upregulation on NK-cells confers inhibitory feedback signals from surrounding MHC-II+ cells to terminate NK-cell suppression of T cells. Uncovering the role of LAG-3 in NK cell immunoregulatory function will provide a novel target to constrain this suppression and enhance vaccine-elicited T cell responses.

Origin and differentiation trajectories of fibroblastic reticular cells in the splenic white pulp

The splenic white pulp is underpinned by poorly characterized stromal cells that demarcate distinct immune cell microenvironments. Here we establish fibroblastic reticular cell (FRC)-specific fate-mapping in mice to define their embryonic origin and differentiation trajectories. Our data show that all reticular cell subsets descend from multipotent progenitors emerging at embryonic day 19.5 from periarterial progenitors. Commitment of FRC progenitors is concluded during the first week of postnatal life through occupation of niches along developing central arterioles. Single cell transcriptomic analysis facilitated deconvolution of FRC differentiation trajectories and indicated that perivascular reticular cells function both as adult lymphoid organizer cells and mural cell progenitors. The lymphotoxin-β receptor-independent sustenance of postnatal progenitor stemness unveils that systemic immune surveillance in the splenic white pulp is governed through subset specification of reticular cells from a multipotent periarterial progenitor cell. In sum, the finding that discrete signaling events in perivascular niches determine the differentiation trajectories of reticular cell networks explains the development of distinct microenvironmental niches in secondary and tertiary lymphoid tissues that are crucial for the induction and regulation of innate and adaptive immune processes.

Splenic portal for lymphocyte entry

Lymphocyte Homing Lymphocytes are immune cells that travel through the body, alternating between periods of residence in lymphoid organs and periods of circulation in blood and lymphatic vessels. Tadayon et al. investigated where circulating lymphocytes first exit the vasculature of the mouse spleen to gain access to the lymphocyte-rich splenic white pulp. Minutes after adoptive transfer of labeled lymphocytes, the majority were found in the red pulp zone of the spleen. The Clever-1 adhesion and scavenger receptor on endothelial cells was an important facilitator of initial entry of B cells and CD8+ T cells into the red pulp. Distinct molecular mechanisms apparently govern how lymphocytes traffic into the spleen compared with the lymph nodes. Sci. Immunol. 4 , eaat0297 (2019).

White Pulp Expansion of the Spleen is correlated with Plasma IL‐6 and Glucose in Mice Fed High‐Fat, High‐Sugar Diet

We previously identified significant splenomegaly in mice fed a diet high in fat and sugar (HFSD) in comparison to mice fed a standard diet. Mice fed HFSD also exhibited elevated blood plasma levels of glucose and the proinflammatory cytokine IL‐6. However, the relationship between these markers and the proliferation of immune tissue in the spleen is unclear. The white pulp of the spleen is a site of immune response and may expand when exposed to proinflammatory signaling molecules. In this study, we investigated the correlations among splenic white pulp area, plasma glucose, and plasma IL‐6. Female C57BL/6 mice aged 6 weeks were randomly divided into lean control (n=4) and HFSD (n=4) groups. HFSD consisted of chow with 60% fat content and drinking water with 42 g/L sugar (55% sucrose, 45% fructose). Treatment was administered for 12 weeks. White pulp area of the spleen was measure from histological sections stained with H&amp;E. Mice in the HFSD group became significantly obese and hyperglycemic by the end of the study (P &lt; 0.05). Mice fed HFSD also had significantly larger splenic white pulps than lean mice (P &lt; 0.05). Splenic white pulp area was positively correlated with blood plasma levels of IL‐6 (r = 0.725, P &lt; 0.05) and glucose (r = 0.686, P &lt; 0.05). Plasma Il‐6 was also positively correlated with plasma glucose levels (r = 0.887, P &lt; 0.01). These data support the hypothesis that HFSD is associated with histological expansion of the white pulp of the spleen that correlates with diet‐induced hyperglycemia and the expression of proinflammatory cytokines.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Aging of Antiviral CD8+ Memory T Cells Fosters Increased Survival, Metabolic Adaptations, and Lymphoid Tissue Homing.

Aging of established antiviral T cell memory can foster a series of progressive adaptations that paradoxically improve rather than compromise protective CD8+ T cell immunity. We now provide evidence that this gradual evolution, the pace of which is contingent on the precise context of the primary response, also impinges on the molecular mechanisms that regulate CD8+ memory T cell (TM) homeostasis. Over time, CD8+ TM generated in the wake of an acute infection with the natural murine pathogen lymphocytic choriomeningitis virus become more resistant to apoptosis and acquire enhanced cytokine responsiveness without adjusting their homeostatic proliferation rates; concurrent metabolic adaptations promote increased CD8+ TM quiescence and fitness but also impart the reacquisition of a partial effector-like metabolic profile; and a gradual redistribution of aging CD8+ TM from blood and nonlymphoid tissues to lymphatic organs results in CD8+ TM accumulations in bone marrow, splenic white pulp, and, particularly, lymph nodes. Altogether, these data demonstrate how temporal alterations of fundamental homeostatic determinants converge to render aged CD8+ TM poised for greater recall responses.

Samsum ant venom modulates the immune response and redox status at the acute toxic dose in vivo.

Background: Ant venoms express surface molecules that participate in antigen presentation involving pro- and anti-inflammatory cytokines. This work aims to investigate the expression of MHC-II, CD80 and CD86 on the polymorphonuclear cells (PMNs) in rats injected with samsum ant venom (SAV).Methods: Rats were divided into three groups - control, SAV-treated (intraperitoneal route, 600 μg/kg), and SAV-treated (subcutaneous route, 600 μg/kg). After five doses, animals were euthanized and samples collected for analysis.Results: The subcutaneous SAV-trated rats presented decreased levels of glutathione with increased cholesterol and triglyceride levels. Intraperitoneal SAV-treated animals displayed significantly reduced concentrations of both IFN-γ and IL-17 in comparison with the control group. However, intraperitoneal and subcutaneous SAV-treated rats were able to upregulate the expressions of MHC-II, CD80 and CD86 on PMNs in comparison with the control respectively. The histological examination showed severe lymphocyte depletion in the splenic white pulp of the intraperitoneal SAV-injected rats.Conclusion: Stimulation of PMNs by SAV leads to upregulation of MHC-II, CD 80, and CD 86, which plays critical roles in antigen presentation and consequently proliferation of T-cells. Subcutaneous route was more efficient than intraperitoneal by elevating MHC-II, CD80 and CD86 expression, disturbing oxidative stability and increasing lipogram concentration.

The Mst1 Kinase Is Required for Follicular B Cell Homing and B-1 B Cell Development.

The Mst1 and 2 cytosolic serine/threonine protein kinases are the mammalian orthologs of the Drosophila Hippo protein. Mst1 has been shown previously to participate in T-cell and B-cell trafficking and the migration of lymphocytes into secondary lymphoid organs in a cell intrinsic manner. We show here that the absence of Mst1 alone only modestly impacts B cell homing to lymph nodes. The absence of both Mst1 and 2 in hematopoietic cells results in relatively normal B cell development in the bone marrow and does not impact migration of immature B cells to the spleen. However, follicular B cells lacking both Mst1 and Mst2 mature in the splenic white pulp but are unable to recirculate to lymph nodes or to the bone marrow. These cells also cannot traffic efficiently to the splenic red pulp. The inability of late transitional and follicular B cells lacking Mst 1 and 2 to migrate to the red pulp explains their failure to differentiate into marginal zone B cell precursors and marginal zone B cells. Mst1 and Mst2 are therefore required for follicular B cells to acquire the ability to recirculate and also to migrate to the splenic red pulp in order to generate marginal zone B cells. In addition B-1 a B cell development is defective in the absence of Mst1.

Ameliorative role of ferulic acid against diabetes associated oxidative stress induced spleen damage

Spleen, a secondary lymphoid organ, is the site of initiation of most of the immune responses. The present study is centered on the ameliorative role of ferulic acid against diabetic complications in the spleen of male Wistar rats. Induction of diabetes by STZ (at a dose of 50 mg kg−1 body wt, i.p.) reduced the spleen size, plasma insulin level, enhanced the blood glucose level and disrupted the intracellular antioxidant machineries along with the depletion of splenic white pulp. Induction of oxidative stress mediated inflammation and apoptosis (upregulation in the levels of inflammatory cytokines, translocation of NF ĸB in the nucleus, alteration in Bax/Bcl-2 ratio, release of cytochrome c from mitochondria, activation of caspase-9 and 3, PARP cleavage and DNA fragmentation) were evidenced from immunoblot analyses, DNA fragmentation and TUNEL assay. However, ferulic acid administration post diabetes induction, (at a dose of 50 mg kg−1 body wt, orally for eight weeks) could reverse such adverse effects. Therefore, ferulic acid, as a potential therapeutic agent may hold promise in evading oxidative stress mediated diabetic splenotoxicity in rats.

Attrition of T Cell Zone Fibroblastic Reticular Cell Number and Function in Aged Spleens.

Aging has a profound impact on multiple facets of the immune system, culminating in aberrant functionality. The architectural disorganization of splenic white pulp is a hallmark of the aging spleen, yet the factors underlying these structural changes are unclear. Fibroblastic reticular cells comprise one stromal cell subset in the spleen that is important for maintenance of architectural organization, yet it remains to be determined how aging impacts these cells. In this study, we sought to determine how aging impacts splenic T cell zone reticular cell (TRC) numbers, morphology, and function. Using a mouse model of aging, we found that aged naive spleens have fewer TRCs than young spleens. This reduction in TRC number correlated with reduced CCL19 and CCL21 concentrations in aged spleens, which may contribute to impaired homing of T cells. CCL21 in both young and aged spleens localized with TRCs. Aged TRCs extended marginally into B cell follicles and may contribute to the blending of the T cell zone and B cell follicles in aged spleens. The described age-related changes in TRCs number and function may be an underlying factor contributing to impaired immune system function with age.