Auswahl der wissenschaftlichen Literatur zum Thema „Non-lymphoid organs“

After development in the thymus, naive T lymphocytes come into circulation and continuously recirculate between the blood and peripheral lymphoid organs for activation and transformation into effector cells. The movement of naive T lymphocytes represents an ordered sequence controlled by the expression of specific of specific proteins (selectin, integrin and chemokine) that includes the recruitment of circulating lymphocytes on the luminal surface of the blood vessel, transendothelial transition and migration within the extravascular compartment of peripheral lymphoid organs. The question of the movement of naive T lymphocytes in and out of non-lymphoid organs in physiological conditions has not been fully resolved. There is an opinion that naive T lymphocytes under physiological conditions routinely access almost all non-lymphoid organs for the purpose of immunosurveillance and/or tolerance induction. Non-lymphoid organs burdened by chronic inflammation and tumor processes may possess a significant number of naive T lymphocytes. Organized lymphoid tissue causally contributes to the persistence of certain autoimmune diseases. Recruitment in tumor tissue and subsequent antitumor immune response correspond with a positive prognosis.

Abstract Tertiary lymphoid organs (TLOs) are ectopic lymphoid structures that arise in non-lymphoid tissues and are frequently observed in tissue affected by non-resolving chronic inflammation. If TLOs are beneficial or detrimental in transplantation is controversial. We investigate the role of TLO and LTbR in transplantation by manipulating the LTa-LTbR pathway. Using a mouse allo kidney transplantation model, we found that preformed intragraft TLO are sufficient to precipitate rejection in recipients lacking all secondary lymphoid organs (SLO)(LTbRko). In WT recipients with a complete set of SLO, intragraft TLO accelerated rejection (MST=63 vs. 225 d). Donor grafts that cannot form TLO (LTbRko) prolonged allograft survival (MST 24 vs 11 d) in an acute kidney rejection model. Intravital imaging confirmed that T and B cell activation takes place in renal TLO upon migration of naïve T and B cells and prolonged interactions with dendritic cells. T cells produced IFNg and Confetti+/+ B cells clonally expanded within TLO. In summary, intragraft TLO are sufficient for and accelerate allograft rejection. Local immune responses are initiated and maintained in intragraft TLO, while disruption of TLO formation in the allograft leads to prolonged allograft survival. TLO support T and B cell activation as well as local DSA formation. These findings highlight the importance of TLO in local immune responses with implications for cancer, autoimmunity and transplantation.

Visna/Maedi virus (VMV), a small ruminant lentivirus responsible for lymphoproliferative pneumonia, encephalitis, arthritis and/or mastitis in sheep, has been detected in different non-lymphoid organs. However, only a few investigations have been carried out in lymphoid tissues. In this study, some lymphoid tissues and lymph node draining or non-draining VMV target organs from five sheep infected experimentally by the respiratory route three years previously were investigated. Archival samples of spleen, red bone marrow, caudal mediastinal lymph nodes, mammary lymph nodes, popliteal lymph nodes and mesenteric lymph nodes were tested by PCR for the presence of proviral DNA. Popliteal and mesenteric lymph node samples were tested also by immunohistochemical staining of the viral capsid antigen p28. The proviral DNA was detected by PCR in all the lymphoid tissue samples from the infected sheep. The viral antigen was stained in mononuclear cells in popliteal and mesenteric lymph nodes of the infected sheep. Although the lymph nodes draining the classical target organs seem to be more infected than the others, both the viral capsid antigen and the proviral DNA were present also in lymph nodes draining non-target organs, such as the mesenteric lymph nodes. These findings show the presence of VMV in different lymphoid tissues in the late stages of infection and suggest a potential role of these tissues as a site for viral reservoir and replication, even three years after infection.  

Abstract After allogeneic hematopoietic cell transplantation (allo-HCT), donor T cells undergo priming in secondary lymphoid tissues followed by migration to different target organs, where they mediate inflammation and cause acute Graft-versus-Host Disease (aGVHD). Here, we characterized T cells infiltrating GVHD-target organs using a model of aGVHD in non-human primates in order to delineate tissue-specific patterns of the alloimmune response. We found that aGVHD profoundly shifted the T cell phenotype from the naïve state toward an effector-memory state in both the blood and secondary lymphoid organs, with an attenuated shift in non-lymphoid organs. However, in all compartments, tissue-infiltrating T cells demonstrated an aGVHD-specific activated phenotype characterized by a high rate of proliferation and elevated effector functions. In addition, transcriptomic profiles of aGVHD- and tissue-residency developed in T cells residing the colon, liver and lungs as well as in the blood. To further delineate the patterns of T cell trafficking and activation during aGVHD, we directly labeled leukocytes in vivo using fluorescent anti-CD45 antibodies. Using this approach, we detected notable changes in T cell trafficking patterns which included increased T cell trafficking to lymph nodes, lungs and kidneys after allo-HCT, with rates of T cell migration to the GI tract unchanged even during aGVHD. These data provides novel insights into the spatial organization of systemic alloimmunity during aGVHD and the organ-specific impact of this disease on T cell trafficking, activation and functional maturation.

Gangliosides are acidic glycosphingolipids localized mainly on the outer membrane layer of the membranous cell structures. These molecules participate in important mechanisms at molecular, cellular, tissue, organ, and organism levels. It has been proven that gangliosides play a role as regulators of various biological processes but also as markers in a number of multifactor pathologies. In this regard, the present study determined the titers of the GM3, GM1, and GD1a gangliosides, as well as the titers of IgG-class antibodies against each of them by enzyme-linked immunosorbent assay (ELISA), in several different anatomic organs: brain, pancreas, myocardium, liver, and small intestine from rodents. A total extract (control sample) containing the complete set of molecules is prepared from each isolated anatomic organ. An equivalent amount of the extract is passed through a GSH-agarose column in order to select the molecules from each organ possessing affinity to the reduced form of glutathione tripeptide (GSH). GSH is known as an antioxidant, immunomodulator, cardioprotector, neuroprotector, hepatoprotector, anticancer, and antiaging agent. As a whole, significantly lower titers of the three gangliosides and the antibodies to them are reported in the myocardium and liver samples compared to the brain and pancreas samples. Taking into account that the myocardium and liver are the organs known with the highest content of GSH, the obtained results can be explained by the possibly high content of free and/or newly synthesized GSH in them, which does not participate in intermolecular interactions compared to the other investigated organs. Complete absence of each of the three tested gangliosides or of antibodies against them at certain dilutions of the small intestine samples, as well as the highest titers of the same parameters compared to the corresponding samples from the other organs of each of the gangliosides or of the specific antibodies at other dilutions, is observed. One of the explanations for those peculiarities is associated with the presence of the intestinal microflora, including the influence of intestinal bacteria neuraminidases (sialidases). The presented data also show a possibility of antibodies/immunoglobulins production by non-lymphoid cells, tissues, and organs in suitable conditions. Since the immunoglobulins thus produced reside outside the germinal centers of the specialized lymphoid tissues and organs, regulation of their production and functions by interactions with small ions and/or molecules is also important. Gangliosides are namely such small molecules. Special attention is paid to intermolecular interactions involving the listed gangliosides and GSH. The main objective is related to understanding the mechanisms underlying the interaction between the individual organs and systems in the body.

La régulation du métabolisme cellulaire est un élément central gouvernant le destin et la fonction des cellules T. Parmi les cellules T, les cellules T régulatrices CD4+ Foxp3+ (Tregs) sont essentielles pour le maintien de la tolérance au soi et de l'homéostasie immunitaire. Les Tregs sont présentes dans les tissus lymphoïdes où elles contrôlent les réponses immunitaires et dans divers tissus non-lymphoïdes où elles maintiennent l'homéostasie tissulaire. Les précurseurs des Tregs colonisant les tissus non-lymphoïdes sont présents dans la rate et les ganglions lymphatiques et subissent des étapes de différenciation développementale. Cependant, les mécanismes par lesquels les Tregs colonisent les tissus non-lymphoïdes et comment les Tregs tissulaires s'adaptent métaboliquement aux différents microenvironnements tissulaires restent mal compris en partie à cause des difficultés expérimentales à évaluer les profils métaboliques de cellules rares dans des conditions physiologiques. Pour étudier le métabolisme des Tregs, des souris knock-out conditionnelles pour le point de contrôle métabolique Liver kinase B1 (LKB1) (cKO) ont été générées. Ces souris ont une durée de vie significativement réduite en raison d'un trouble hyperinflammatoire systémique, malgré un nombre relativement normal de Tregs dans la rate et les ganglions lymphatiques. LKB1, principalement connu pour activer AMPK et moduler le métabolisme mitochondrial, semble crucial pour la colonisation des tissus non-lymphoïdes par les Tregs. Une analyse plus approfondie a révélé l'absence des précurseurs des Tregs tissulaires matures dans la rate des souris cKO, suggérant un blocage de la différenciation des Tregs tissulaires en l'absence de LKB1.Des avancées récentes, telles que la technique SCENITH, permettent d'étudier le métabolisme des cellules rares en mesurant la traduction des protéines comme indicateur de la consommation d'énergie par cytométrie en flux. Cependant, cette technique nécessite traditionnellement que les cellules soient cultivées ex vivo ou in vitro, ce qui peut altérer leur métabolisme. Pour résoudre ce problème, une méthode innovante dérivée de SCENITH a été mise en œuvre pour investiguer le métabolisme cellulaire des cellules T dans la rate et les poumons à l'état stationnaire. Comparée à la SCENITH classique, cette nouvelle technique aide également à améliorer la viabilité des cellules, en particulier pour les Tregs. Les résultats obtenus avec la SCENITH in vivo ont révélé que les cellules T conventionnelles et les Tregs partagent des profils métaboliques similaires dans la rate et les poumons. Notamment, le métabolisme des cellules T pulmonaires repose principalement sur la phosphorylation oxydative à l'état stationnaire, tandis que les cellules T spléniques utilisent également la glycolyse. De plus, le maintien de l'expression de Foxp3 dans les Tregs est influencé par les inhibiteurs métaboliques affectant la traduction des protéines et la disponibilité énergétique. Nos résultats soulignent le rôle de LKB1 dans la différenciation et la colonisation des Tregs tissulaires et mettent en avant l'importance de l'adaptation métabolique dans la différenciation des Tregs tissulaires. La nouvelle technique SCENITH in vivo pourrait fournir des informations précieuses pour évaluer l'état métabolique des cellules T rares dans leurs environnements naturels
Regulation of cellular metabolism is a central element governing the fate and function of T cells. Among T cells, CD4+ Foxp3+ regulatory T cells (Tregs) are critical for the maintenance of self-tolerance and immune homeostasis. Tregs are present in lymphoid tissues where they control immune responses and in various non-lymphoid tissues where they maintain tissue homeostasis. Precursors of Tregs colonising non- lymphoid tissues are present in the spleen and lymph nodes and undergo developmental differentiation steps. However, the mechanisms by which Tregs colonise non-lymphoid tissues and how tissue Tregs metabolically adapt to varying microenvironments across tissues remain poorly understood partly because of experimental difficulties in assessing the metabolic profiles of rare cells in physiological conditions. To investigate the metabolism of Tregs, mice conditionally knocked out for the metabolic checkpoint Liver kinase B1 (LKB1) (cKO) were generated. These mice have a significantly reduced lifespan due to a systemic hyperinflammatory disorder, despite having relatively normal numbers of Tregs in the spleen and lymph nodes. LKB1, primarily known for activating AMPK and modulating mitochondrial metabolism, appears crucial for the colonisation of NLT by Tregs. Further analysis revealed the absence of the mature tissue Treg precursors in the spleen of cKO mice, suggesting a block of tissue Treg differentiation in the absence of LKB1.Recent advances, such as the SCENITH technique, allow the study of the metabolism of rare cells by measuring protein translation as an indicator of energy consumption by flow cytometry. However, this technique traditionally requires cells to be cultured ex vivo or in vitro, which can alter their metabolism. To address this issue, an innovative method derived from SCENITH was implemented to investigate the cellular metabolism of T cells in the spleen and lungs at steady state. Compared to classical SCENITH, this new technique also helps improve cell viability, in particular for Tregs. Results obtained with the in vivo SCENITH revealed that conventional T cells and Tregs share similar metabolic profiles in the spleen and lungs. Notably, lung T cell metabolism relies mainly on oxidative phosphorylation at steady state, while spleen T cells also utilise glycolysis. Additionally, maintaining Foxp3 expression in Tregs is influenced by metabolic inhibitors affecting protein translation and energy availability. Our findings highlight the role of LKB1 in the differentiation and colonisation of tissue Tregs and underscore the importance of metabolic adaptation in tissue Treg differentiation. The new in vivo SCENITH technique may provide valuable insights to assess the metabolic status of rare T cells in their natural environments

Non-Hodgkin lymphomas (NHL) are a heterogeneous group of malignancies originating from B- or T-lymphocytes and engaging lymphoid tissue. Clinically, NHL subtypes range from chronic indolent to aggressive life-threatening diseases. The incidence of NHL overall increased dramatically worldwide during the latter half of the twentieth century but has now leveled off in many countries. Although some etiologic factors have been identified, most newly diagnosed cases of NHL as well as the previous rise in incidence remain largely unexplained. Well-established risk factors include severe immune suppression following HIV/AIDS and organ transplantation, autoimmune and inflammatory disorders, some infectious agents, and family history. More recently, lifestyle factors have also been linked with certain subtypes of NHL. Through the work of the international InterLymph consortium, several subtype-specific genetic susceptibility variants have also been revealed, promising to shed further light on mechanisms of lymphomagenesis.

The gastrointestinal (GI) system is responsible for digestion and absorption, but also has important endocrine, immune and barrier functions. Additionally, the GI system plays a major role in fluid, electrolyte and acid-base balance. The GI system is regulated by complex myogenic, neural and humoral mechanisms, and, in health, these are affected by the presence of luminal nutrient, thereby modulating function of the GI system. Accordingly, GI function varies depending on whether a person is fasted or in the postprandial state. Adequate fasting and postprandial perfusion, motility and exocrine secretion are required for ‘normal’ functioning. The protective mechanisms of the GI system consist of physical (intact gut mucosa), non-immune (gastric acid, intestinal mucin, bile and peristalsis) and immune (gut-associated lymphoid tissue, GALT) elements. Disruption of GI protection is a putative mechanism underlying the development of multiple-organ dysfunction syndrome. Maintenance of GI function is increasingly recognised as an important factor underlying survival in critical illness.

Blood is a dynamic fluid consisting of cellular and plasma components undergoing constant regeneration and recycling. Like most physiological systems, the concentrations of these components are tightly regulated within narrow limits under normal conditions. In the critically-ill population, however, haematological abnormalities frequently occur and are largely due to non-haematological single- or multiple-organ pathology. Haematopoiesis originates from the pluripotent stem cell, which undergoes replication, proliferation, and differentiation, giving rise to cells of the erythroid, myeloid, and lymphoid series, as well as megakaryocytes, the precursors to platelets. The haemostatic system is responsible for maintaining blood fluidity and, at the same time, prevents blood loss by initiating rapid, localized, and appropriate blood clotting at sites of vascular damage. This system is complex, comprising both cellular and plasma elements, i.e. platelets, coagulation and fibrinolytic cascades, the natural intrinsic and extrinsic pathways of anticoagulation, and the vascular endothelium. A rapid, reliable, and inexpensive method of examining haematological disorders is the peripheral blood smear, which allows practitioners to assess the functional status of the bone marrow during cytopenic states. Red blood cells, which are primarily concerned with oxygen and carbon dioxide transport, have a normal lifespan of only 120 days and require constant erythropoiesis. White blood cells represent a summation of several circulating cell types, each deriving from the hematopoietic stem cell, together forming the critical components of both the innate and adaptive immune systems. Platelets are integral to haemostasis, and also aid our inflammatory and immune responses, help maintain vascular integrity, and contribute to wound healing.

AbstractNon-Hodgkin lymphomas (NHLs) are a heterogeneous group of lymphoid neoplasms with different biological characteristics. About 90% of all lymphomas in the United States originate from B lymphocytes, while the remaining originate from T cells [1]. The treatment of NHLs depends on the neoplastic histology and stage of the tumor, which will indicate whether radiotherapy, chemotherapy, or a combination is the best suitable treatment [2]. The American Cancer Society describes the staging of lymphoma as follows: Stage I is lymphoma in a single node or area. Stage II is when that lymphoma has spread to another node or organ tissue. Stage III is when it has spread to lymph nodes on two sides of the diaphragm. Stage IV is when cancer has significantly spread to organs outside the lymph system. Radiation therapy is the traditional therapeutic route for localized follicular and mucosa-associated lymphomas. Chemotherapy is utilized for the treatment of large-cell lymphomas and high-grade lymphomas [2]. However, the treatment of indolent lymphomas remains problematic as the patients often have metastasis, for which no standard approach exists [2].

Immunosuppressive non-oncogenic viral diseases in poultry birdscause heavy mortality and huge economic losses in infected chickens thus posing a great risk to poultry industry. Increased susceptibility to secondary infections and deficient response to vaccination further complicates the condition. This chapter provides an overview of various non-oncogenic immunosuppressive viral diseases of chickens with special emphasis on their transmission, pathogenesis and considerable immunosuppressive effect produced by such diseases. The important immunosuppressive diseases discussed in this chapter include Chicken Infectious Anaemia (CIA), Infectious Bursal Disease (IBD), Avian Reoviral (ARV) and Fowl Adenoviral (FAdV) diseases. CIA virus, ARV and FAdV follow both trans-ovarian route as well as horizontal route of transmission. However, IBD virus is transmitted only by horizontal route. CIA virus produces the immunosuppressive effect either alone or in combination with other viruses causing increased mortality, severe anaemia and generalized lymphoid atrophy. The virus replicates in lymphoid and erythroid progenitor cells, causing their severe depletion anddistinct sub-clinical infections. IBD virus replicates in IgM+ cells of bursa of Fabriciusand leads to destruction of bursal follicles causing immunosuppression. The mortality by IBD virus is variable and depends upon age of the chicken and more specifically virulence of the virus. ARVs and FAdV are opportunistic viruses and usually occur in combination with other immunosuppressive viruses. ARV commonly causes malabsorption syndrome, enteric disease, viral arthritis/tenosynovitis, stunting/runting syndromes, immunosuppression, and respiratory disease in young chickens. The virus interacts with B-lymphocytes in a similar manner as in IBDV, thus, producing lesions in bursa and other lymphoid organs. FAdV is an immuno suppressive pathogen, whichcauses Hydropericardium syndrome (HPS) and Inclusion body hepatitis (IBH) in 3–6-weeks old broilers. Mixed infections of immunosuppressive viruses are common, as compared to the individual infections. This results in synergic pathological effects that further deteriorates the health of the infected chickens. Proper vaccination strategies, diagnostic approaches and control measures should be followed to prevent the occurrence of such infections.

Post-transplant lymphoproliferative disease (PTLD) is a disorder of lymphoid proliferation seen in recipients of solid organ or haematopoietic transplants as a consequence of immunosuppression. A spectrum of disease is recognized ranging from non-malignant polyclonal proliferation of B cells to monoclonal proliferation of B or T lymphocytes which have features in common with lymphomas. Epstein–Barr virus (EBV) is associated with a majority of cases although it is not a universal feature. Treatment with anti-CD20 antibody in addition to reduction in immunosuppression has become the most common treatment approach.

Abstract Non-Hodgkin’s lymphoma (NHL) of the gastrointestinal (GI) tract accounts for 4% to 20% of all NHL, making the GI tract the most common extranodal site of NHL presentation. Most of these lymphomas arise from mucosa-associated lymphoid tissue (MALT). The stomach is the primary organ involved in GI lymphoma, representing more than 70% of cases of primary GI lymphoma in the United States; the remaining cases involve the small or large bowel.2,3 In a study reported by Papachristodoulou and colleagues, 66% of the MALT lymphomas occurred in the stomach, 29% occurred in the jejunum and ileum, and 6% occurred in the colon.

Primary gastrointestinal lymphoma is the most common extranodal lymphoma and is almost exclusively of non-Hodgkin type. It is defined as lymphoma that has presented with the main bulk of disease in the gastrointestinal tract, with or without involvement of contiguous lymph nodes. MALT lymphoma is an indolent B-cell lymphoma whose histology recapitulates the features of mucosa-associated lymphoid tissue (MALT). It most commonly affects the stomach, presenting with nonspecific dyspepsia. Most cases appear to be driven by Helicobacter pylori, with 75% regressing following eradication of the organism with appropriate antibiotics. Deeply invasive lymphomas and those with adverse histological or cytogenetic features are unlikely to respond. Mantle cell lymphoma and follicular lymphoma are adult B-cell lymphomas that can present as gastrointestinal lymphomas. Diffuse large B-cell lymphoma is an aggressive lymphoma that is relatively frequently encountered in gastrointestinal locations. Burkitt’s lymphoma is also an aggressive B-cell lymphoma, and is the most frequent childhood gastrointestinal lymphoma. Enteropathy-associated T-cell lymphoma is an intestinal lymphoma of intraepithelial T lymphocytes that occurs most commonly in the jejunum or ileum and is associated with coeliac disease. It presents with abdominal pain, often due to intestinal perforation. The prognosis is usually poor, with death frequently resulting from abdominal complications in patients already weakened by uncontrolled malabsorption.

Leukostasis is a life-threatening condition that occurs when leukemia cells accumulate in the vasculature of organs such as the brain and lungs. Recent evidence has shown that leukostasis is not simply due to the physical overcrowding of leukemia cells, as previously thought, but may result from specific mechanical properties of the cells and interactions between cells. Using atomic force microscopy (AFM), we obtained direct measurements of two mechanical properties that are likely involved in this condition: (1) stiffness of individual leukemia cells and (2) non-specific adhesion forces between leukemia cells. We found that myeloid leukemia cells were significantly stiffer than lymphoid leukemia cells. Cell-cell adhesion forces of the cell lines were not found to be statistically different. These results may help to explain the clinical observation that leukostasis occurs in myeloid leukemia at lower white blood cell counts than in lymphoid leukemia.