Lymph nodes are encapsulated, vascularized secondary lymphoid organs with anatomic features that favor the initiation of adaptive immune responses to antigens carried from tissues by lymphatics. Lymph nodes located along lymphatic vessels act as filters that sample the lymph for soluble and DC-associated antigens. The captured antigens can then be seen by cells of the adaptive immune system. There are approximately 500 lymph nodes in the human body. A lymph node (Fig. 1) is surrounded by a fibrous capsule, beneath which is a system of sinuses that are lined by reticular cells and supported by fibrils of collagen and other extracellular matrix proteins. These sinuses are filled with lymphocytes, macrophages, DCs, and other cell types. Afferent lymphatics empty into the subcapsular sinus and lymph may drain from there directly into the connected medullary sinus and then out of the lymph node through the efferent lymphatics. Macrophages in the subscapular sinus provide an important function of phagocytosing and removing infectious organisms, which they can recognize by several types of cell surface receptors. Beneath the inner floor of the subcapsular sinus is the lymphocyte-rich cortex. The outer cortex contains aggregates of cells called follicles that are populated mainly by B lymphocytes. The inner cortex adjacent to the follicles, called the parafollicular cortex, paracortex, or T-cell zone, is organized into cords, with abundant extracellular matrix proteins and fibers, and is populated mainly by T lymphocytes.

Fig1. Morphology of a lymph node. (A) Schematic diagram of a lymph node illustrating the T cell–rich and B cell–rich zones and the routes of entry of lymphocytes and antigen (shown captured by a dendritic cell). (B) Light micrograph of a lymph node illustrating the T-cell and B-cell zones. Courtesy Robert Oghami, MD, PhD, and Kaushik Sridhar, Department of Pathology, University of California, San Francisco.

The development of lymph nodes, as well as of other secondary lymphoid organs, depends on lymphoid tissue–inducer cells and the coordinated actions of several cytokines, chemokines, and transcription factors. During fetal life, lymphoid tissue–inducer cells, which are a subset of ILCs that were dis cussed earlier, stimulate the development of lymph nodes and other secondary lymphoid organs. This function is mediated by various proteins expressed by the inducer cells, the most thoroughly studied being the membrane-bound molecule lymphotoxin α2β, which is a trimer consisting of one α chain and two β chains. Mice with genetic deletions in either the α or β chain do not develop lymph nodes or secondary lymphoid tissues in the gut. Splenic white pulp development is also disorganized in these mice. Lymphotoxin produced by the inducer cells stimulates stromal cells in different locations of a developing secondary lymphoid organ to secrete chemokines that help to organize the structure of the lymphoid organs.

Anatomic Organization of B and T Lymphocytes in Lymph Nodes

B and T lymphocytes are sequestered in distinct regions of the cortex of lymph nodes (Fig. 2). B cells are found mainly in the cortical follicles. Some follicles contain central areas called germinal centers, which stain lightly with commonly used histologic stains. Follicles without germinal centers, called primary follicles, contain mostly mature, naive B lymphocytes. Follicles with germinal centers, called secondary follicles, contain activated B cells. Germinal centers develop in response to antigenic stimulation and are sites of remarkable B-cell proliferation, selection of B cells producing high-affinity antibodies, and generation of memory B cells and long-lived plasma cells. Each germinal center consists of a dark zone packed with proliferating B cells called centroblasts and a light zone containing cells called centrocytes that have stopped proliferating and are being selected to survive and differentiate further.

Fig2. Segregation of B cells and T cells in a lymph node. (A) The schematic diagram illustrates the path by which naive T and B lymphocytes migrate to different areas of a lymph node. The naive lymphocytes enter the node through an artery, leave the circulation by moving across the wall of the high endothelial venule (HEV), and then the B and T cells migrate to different zones of the lymph node drawn by chemokines that are produced in these areas and bind selectively to chemokine receptors specific for each cell type. Also shown is the migration of dendritic cells, which pick up antigens from the sites of antigen entry, enter through afferent lymphatic vessels, and migrate to the T cell–rich areas of the node. (B) In this section of a lymph node, the B lymphocytes, located in two follicles, are stained red; the T cells, in the parafollicular cortex, are blue. Dendritic cells, in the parafollicular cortex, are also stained red. The method used to stain these cells is called immunofluorescence. The anatomic segregation of T and B cells is also seen in the spleen. Courtesy Andrea Radtke, PhD, Laboratory of Ronald N. Germain, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

T lymphocytes are located mainly beneath and more centrally to the follicles in the paracortical cords. Naive T cells enter the T-cell zones through specialized cortical blood vessels called high endothelial venules (HEVs), described in detail in Chapter 3, and T cells are densely packed around the HEVs. Most (∼70%) of the cortical T cells are CD4+ helper T cells, intermingled with fewer CD8+ cells. These proportions can change dramatically during the course of an infection. For example, during a viral infection, there may be a marked increase in CD8+ T cells. DCs that have captured antigens in peripheral tissues also migrate to the T cell zone of the lymph node, where they can present antigens to the T cells.

The anatomic segregation of B and T lymphocytes in dis tinct areas of the node is dependent on chemokines (chemoattractant cytokines) secreted by specialized cells located in each area that direct the migration of the lymphocytes (see Fig. 2). These specialized cells are fibroblastic reticular cells (FRCs) in the T-cell zones and follicular dendritic cells (FDCs) in the follicles. FRCs are mesenchymally derived myofibroblasts that drive the formation of secondary lymphoid organs during embryonic development and contribute in multiple ways to the functions of these organs. Several subtypes of FRCs are located in different places within secondary lymphoid organs. Most FRCs in lymph nodes can be identified by expression of podoplanin, a glycoprotein that may facilitate adhesion of the FRCs to the stromal reticular (connective tissue) scaffold. The types of FRC that play central roles in maintaining the structure and functions of lymph nodes include marginal reticular cells that form the subcapsular sinus floor, perivascular reticular cells that form layers around HEVs, T-cell zone FRCs that direct movement of T cells and DCs within the lymph node, and B-cell zone FRCs that direct movement of B and T cells in and out of B-cell follicles. FDCs are derived from an FRC precursor and play essential roles in maintaining the structure of lymphoid follicles as well as in B-cell activation.

Chemokines are a large family of 8- to 10-kD cytokines that are involved in organizing the movement of cells in development of organs (including lymphoid organs, the heart, and others), maintenance of tissue architecture, and immune and inflammatory responses. Chemokines bind to receptors on leukocytes and stimulate the cells to move up concentration gradients of the chemokine. Chemokines also induce increases in the affinity of adhesion molecules called intergins, which enhance the migration of leukocytes out of blood vessels. The production of particular chemokines in different areas of secondary lymphoid organs and the expression of receptors for these chemokines determine where B and T cells reside in these organs. Naive T cells express a receptor called CCR7 that binds the chemokines CCL19 and CCL21, which are produced by T-cell zone FRCs. These chemokines promote naive T-cell movement from the blood, through the wall of the HEVs, into the T-cell zone. DCs that are activated by microbes also express CCR7, and lymphatic endothelial cells express CCL21; this is why DCs enter the node through lymphatics, and why they migrate to the same area of the node as do naive T cells. Naive B cells express low levels of CCR7 and higher levels of another chemokine receptor, CXCR5, which recognizes a chemokine, CXCL13, produced by B-cell zone FRCs and FDCs. Thus, circulating naive B cells that enter lymph nodes, also through HEVs, are attracted first into the paracortex by CCR7 engagement, and then rapidly into the follicles in a CXCR5-dependent manner. The functions of chemokines in regulating where lymphocytes are located in lymphoid organs and in the formation of these organs have been established by numerous studies in mice. For example, CXCR5 knockout mice lack B cell–containing follicles in lymph nodes and spleen, and CCR7 knockout mice lack T-cell zones.

The anatomic segregation of B and T cells ensures that each lymphocyte population is in close contact with the appropriate APCs (i.e., B cells with FDCs and T cells with DCs). Furthermore, because of this precise segregation, B- and T-lymphocyte populations are kept apart until it is time for them to interact in a functional way. As we will see in Chapters 9 and 12, after stimulation by protein antigens, B and T cells change their expression of chemokine receptors and begin to migrate toward one another in response to signals from chemokines and other mediators. Activated T cells either migrate toward follicles to help B cells or exit the node and enter the circulation. Activated B cells migrate into germinal centers and, after differentiation into plasma cells, may home to the bone marrow.

T-cell zone FRCs maintain lymph node structure and function by forming a network of specialized tube-like structures called FRC conduits (Fig. 3). These conduits range in diameter from 0.2 to 3 μM and contain organized arrays of extracellular matrix molecules secreted by the FRCs, including parallel bundles of collagen fibers embedded in a meshwork of fibrillin microfibers, all tightly surrounded by a basement membrane produced by a sleeve of FRCs. The FRC conduits display chemokines on their surfaces and act as tracks along which T cells and DCs migrate, responding to the chemokines. The FRC conduits also carry some antigens that enter the lymph nodes through afferent lymphatics into the T-cell zone for access to antigen-presenting DCs. The conduits begin at the subcapsular sinus and extend to both medullary sinus lymphatic vessels and cortical HEVs.

Fig3. Microanatomy of the lymph node cortex. (A) Schematic of the microanatomy of a lymph node showing locations of fibroreticular cells (FRCs) and depicting the route of lymph drainage from the subcapsular sinus, through FRC conduits, to the perivenular channel around the high endothelial venule (HEV). (B) Transmission electron micrograph of an FRC conduit surrounded by fibroblast reticular cells (arrowheads) and adjacent lymphocytes (L). (C) Immunofluorescent stain of an FRC conduit formed of the basement membrane protein laminin (red) and collagen fibrils (green). B, From Gretz JE, Norbury CC, Anderson AO, Proudfoot AEI, Shaw S. Lymph-borne chemokines and other low molecular weight molecules reach high endothelial venules via specialized conduits while a functional barrier limits access to the lymphocyte microenvironments in lymph node cortex. J Exp Med. 2000;192:1425–1439; C, From Sixt M, Nobuo K, Selg M, Samson T, Roos G, Reinhardt DP, et al. The conduit system transports soluble antigens from the afferent lymph to resident dendritic cells in the T cell area of the lymph node. Immunity. 2005;22:19–29.

Antigen Transport Through Lymph Nodes

 Lymph-borne substances that enter the subcapsular sinus of the lymph node are delivered to DCs, macrophages, and FDCs to initiate T- and B-cell responses. The floor of the subcapsular sinus is constructed in a way that permits cells in the sinus to contact or migrate into the underlying cortex but does not allow soluble molecules in the lymph to freely pass into the cortex. Microbes and high-molecular-weight antigens are taken up by sinus macrophages and are presented to cortical B lymphocytes just beneath the sinus. This is the first step in antibody responses to these antigens. Low-molecular-weight soluble antigens are transported out of the sinus through the FRC conduits and passed to resident cortical DCs located adjacent to the conduits. The resident DCs extend processes between the cells lining the conduits and into the lumen and use these processes to capture and ingest the soluble antigens that have entered the conduits. This pathway of antigen delivery may play a role in initial T-cell immune responses to some microbial antigens, but larger and sustained responses require delivery of antigens to the node by tissue DCs, as discussed in Chapter 6.

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مركز السيد جعفر الحلي يواصل تقديم خدماته الصحية للزائرين

العتبة العباسية المقدسة تحيي ذكرى هدم قبور أئمّة البقيع (عليهم السلام) في الصحن الشريف

تقديم المحاضرة السادسة من محفل نهج البلاغة الأسبوعي في بغداد

المزيد

الآخبار الصحية

اكتشاف هام قد يمهّد لعلاج جديد للسمنة

تغييرات بسيطة في نمط الحياة تقلل خطر أمراض القلب بنسبة كبيرة

ليس اللب فقط!.. قشرة وبذور المانغو تخفي فوائد صحية مذهلة

زيادة استهلاك الكالسيوم ومنتجات الألبان يحمينا من مشكلات صحية خطيرة

المزيد

الآخبار التكنلوجية

العلماء الروس يكتشفون طريقة تحسن فرص نجاح زراعة الأسنان

لحظة زمنية خاطفة في الدماغ تتحكم في التعلم والحركة

القمر لم يعد مجرد محطة.. خطوة جديدة تغيّر مستقبل البشرية

العلماء يكتشفون "نوعا جديد تماما" من الكواكب

المزيد

مواضيع ذات صلة

Toll-Like Receptors

Anatomy and Functions of Lymphoid Tissues : Bone Marrow

Populations of Lymphocytes Distinguished by History of Antigen Exposure

Development of Lymphocytes

Dendritic Cells

Mast Cells, Basophils, and Eosinophils

Phagocytes

Major Features of Cell-Mediated Immunity

Major Features of Humoral Immunity

Initiation and Development of Adaptive Immune Responses

Chemokines and Chemokine Receptors

Overview of Humoral and Cell-Mediated Immunity