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Histology Lecture
BSMT 2-B | PRE-FINAL TOPIC | SEM 1 2022 - 2023
LYMPHATIC SYSTEM
● Body is always in constant threat of invasion by microorganisms and substances thus, the body employs several lines of defense ● The first lines of defense are skin and mucous membranes ➔ Skin - acts as a physical barrier; impenetrable unless injured/open wounded ➔ Mucous Membrane - have structural and physiological factors that help in protecting (mucus, cilia, tears, and saliva) ● If the first line of defense fails, 2 defense systems arise Inflammatory Response and Immune Response Inflammatory Response ● Is an immediate but mainly localized process that starts within minutes of tissue damage or entry of a microorganism or a foreign antigen. ● The effector cells of this process consist primarily of phagocytes, mainly neutrophils, and macrophages. They are assisted in carrying out the process by a host of other cells including eosinophils, basophils, mast cells NK cells, and T-cells. ● These cells destroy invading organisms and foreign antigens by phagocytosi s or by releasing substances in their secretory granules that are toxic to the offending substances or organisms. ● The inflammatory response is turned on in a variety of ways. Sometimes, invading microorganisms betray their presence by producing chemotaxins, chemicals that attract phagocytes. At other times, foreign organisms or substances are detected by the complement system. ➔ Complement System - a collection of more than 20 plasma proteins that are produced by the liver. These proteins constitute an enzyme cascade. ● In the immune response, it is activated by and complements the work of, the antibodies (immunoglobulins), ● In inflammation, it spontaneously gets activated in presence of microorganisms and foreign substances ➔ Has the following effects: ➔ Production of Chemotaxins ; marking off of bacteria with Proteins ( opsonins ) to facilitate phagocytosis ➔ Releasing cytokines (proteins that act Signaling compounds) and triggering the release Of other mediators of inflammation such as histamine by mast cells and basophils. ● Once the inflammatory process has hen triggered, activated phagocytes congregate in the injured area within minutes. Thereafter, they start to engulf and digest the invading microorganisms or other foreign elements. ● In addition, macrophages and other antigen-presenting cells (APCs ) which have limited phagocytic activity process the antigens they have digested. Then they attach some parts of the antigens on their surface for presentation to T-cells , the first step in the immune response ● The cytokines and other mediators started during the inflammatory process are responsible for the classical local signs and symptoms of inflammation. They also contribute to the systemic signs and symptoms associated with the process such as fever.
Histology Lecture
BSMT 2-B | PRE-FINAL TOPIC | SEM 1 2022 - 2023
● Fever occurs when interleukin-1, a cytokine produced by activated macrophages enters the bloodstream and reaches the hypothalamus , the temperature-regulating center in the brain. ● The hypothalamus then responds by increasing body temperature. Immune Response (Immunological Response) ● The immune response is a more powerful body defense system than the inflammatory response. ● However, if the invading antigen is a new one (i.e., it has not previously entered the body), it takes longer time than the latter to mount because, unlike inflammation, the immune response is not innate ; it must be developed. ● It is antigen-specific (which means it must be developed for every antigen that the body encounters for the first time) ● Antigens vary in size and composition: ➔ from few amino acids to large and complex antigenic systems (e.g. bacteria, viruses, fungi, parasites, and toxins)
● The principal effector cells of the
immune response are the lymphocytes
(aids in carrying out the process by a
variety of cells). Most of them are
effector cells of the inflammatory
response.
● The body has about two trillion
lymphocytes , accounting for about 1%
of body weight.
● Lymphocytes are capable of conferring
immunity against as many as different
antigens.
CLASSIFICATION
● Lymphocytes are classified into three types (based on the antigen receptors present on their surfaces) A. B-cells have B-cell antigen receptors (BCR), B. T-cells carry T-cell antigen receptors (TCR), and C. NK cells carry natural cytotoxicity receptors (NCR).
● Aside from these receptors, lymphocytes
also possess other surface markers or
receptors.
A. All T-cells, for example, express the
CD3 molecular complex which is
responsible for signal transmission
and mediated via the T-cell receptor
(TCR).
B. Has either CD4 or CD8 markers.
I. Those with CD4 markers (CD4+
T-cells) can differentiate into
helper T-cells (T, cells).
Histology Lecture
BSMT 2-B | PRE-FINAL TOPIC | SEM 1 2022 - 2023
- Antigen Recognition
- Lymphocyte Activation
- Effector Phase ANTIGEN RECOGNITION ● Antigen-presenting cells (APC) are cells that phagocytose, destroy and process antigen on their surface ● Displays fragments of the antigen on their surface for presentation to naïve CD4+ T-cells. ● Essential elements of the immune system ● Naïve CD4+ T-cells do not differentiate into Th cells unless they are presented with an antigen by an APC. Likewise, naïve B-cells do not react to an antigen unless they are activated by cytokines produced by helper T-cells. ● Naïve CD8+ T-cells also do not differentiate into Tc cells unless they are activated by APCs or helper T-cells. ● Many cells of the body including endothelial cells and NK cells can present antigens to T-cells ● “Professional” APCs, macrophages, dendritic cells, and B-cells , can deliver two signals (antigen signal and co-stimulatory signal) needed by naïve CD4+ T-cells for activation. ● Other APCs deliver only the antigen signal, which all APCs do when they attach an antigen on their cell surface ● Co-stimulatory signal can only be provided by an APC to a T-cell if other molecules on the surface of a T-cell can bind to corresponding molecules on the APC ● Macrophages are effector cells of the inflammatory response and are APCs. They do not simply destroy antigens, but process them and attach them to their surface for presentation to naïve T-cells ● Dendritic cells(DCs) comprise a family of APCs that derive their name from the branched projections (dendrites) they exhibit as mature cells. They are the most potent of APCs, widely distributed around the organs, have limited capacity for phagocytosis, and attach antigenic materials on their surface for presentation to naïve CD4+ T-cells. ● DCs are classified into broad categories:
- Myeloid-related
- Lymphoid-related ● Myeloid-related DC (mDC ) differentiates from the colony-forming unit-monocyte/dendritic cells, a progenitor cell that shares with monocyte, and Langerhans cells that are present in the epidermis of the skin and other stratified squamous epithelia. ● Lymphoid-related dendritic cells are DCs found in lymphoid tissues. ● B-cells often act as APCs. Able to do so when a new antigen binds a receptor that is present on its surface. They can phagocytose, process antigen, and attaches parts of the antigen on their surface. ● Despite the presence of antigen on its surface, a naïve B-cell does not get activated unless it interacts and receives the appropriate signal from a Th cell. LYMPHOCYTE STIMULATION ● When naïve CD4+ T-cells are presented with an antigen by APCs in the presence of co-stimulators, they proliferate and differentiate into any or all following cell types: ➔ Th1 cells that synthesize cytokines needed for cell-mediated immunity ➔ Th2 cells that synthesize cytokines needed for humoral immunity ➔ Th3 cells that elaborate cytokine that mediates the inflammatory process EFFECTOR PHASE ● Humoral immunity, Th2 cells encounter naïve B-cells that have the same new antigen on their surface, they interact with the naïve B-cells and release the appropriate cytokines to activate the B-cells. ● Activated B-cells proliferate and their progenies differentiate into plasma cells and memory B-cells
Histology Lecture
BSMT 2-B | PRE-FINAL TOPIC | SEM 1 2022 - 2023
● Plasma cells produce antibodies, while memory b-cells carry the image of the antigen and are responsible for affecting second immune response ● Some antigens are T-cell independent and are able to activate naïve B-cells on their own. ● Cellular immunity where Th1 cells secrete a variety of cytokines that stimulate CD8+ T-cells to proliferate. ● After 4-5 days of proliferation, CD8+ T cells differentiate into cytotoxic T-cells (Tc cells), memory T-cells, and suppressor T-cells (Ts cells) ● Tc cells are effector cells of cellular immunity, while Memory T-cells are similar to Memory B-cells where it carries the image of the antigen and responsible for effecting second immune response ● Suppressor T-cells (Ts cells) inhibit or regulate the activity of B-cells and other T-cells to ensure that an immune response does not get out of hand. ● After eradicating the offending antigen, all remaining antigenic specific cells, except memory cells, undergo apoptosis. Secondary Immune Response ● It is elicited by re-exposure to an antigen that has previously triggered a primary immune response. ● It has a relatively short induction phase of 1 to 2 days and a more rapid build-up. ● This is because when the memory B- cells or memory T-cells that differentiated during the primary immune response encounter the specific antigen in their memory, they are able to immediately recognize it and rapidly divide and differentiate into effector cells such as plasma cells and T-cells, respectively while at the same time, renewing their number. ● The secondary immune response is so effective that pathogenic microorganisms are eliminated before the person manifests any symptoms. ● In addition as in the primary immune response once the offending antigen in the secondary immune response has been eradicated, all the remaining antigenic-specific cells die by apoptosis, except for the memory cells. Abnormal Immune Response ● The immune response is vital to survival but it sometimes goes awry. ● Overwhelming reaction to antigen causes allergic reactions that are occasionally fatal, as in cases of anaphylactic shock following bee stings.
Histology Lecture
BSMT 2-B | PRE-FINAL TOPIC | SEM 1 2022 - 2023
Nodular Lymphoid Tissue ● Refers to the lymphoid tissue where clustered lymphocytes form discrete ovoid masses or lumps known as the lymphoid nodules. ● In lymphoid nodules, the lymphocytes are mainly B-cells. ● Lymphoid nodules begin to appear only at birth. ● Can be found in some lymphoid organs (spleen, lymph nodes), in the lamina propria , and submucosa of the gastrointestinal , respiratory , and genitourinary tracts. ➔ In the lamina propria and submucosa, lymphoid nodules can occur singly (solitary nodules), or in aggregates as in the ileum called Peyer’s patches. ● There are two types of lymphoid nodules under the light microscope : primary and secondary. ➔ Secondary nodule, the lymphocytes react to an antigen, and it has two distinct regions : a pale central area known as the germinal center or reaction center , and a darker peripheral region called the corona. ➔ The germinal center is populated mainly by activated B-cells which undergo proliferation and functional differentiation after exposure to antigen. It is paler than the corona because the lymphocytes are actively-binding and young. ➔ While on the primary nodule, the lymphocytes are idle or resting , and do not have a germinal center , and the lymphocytes present here are all small and are evenly distributed throughout the nodule.
Histology Lecture
BSMT 2-B | PRE-FINAL TOPIC | SEM 1 2022 - 2023
Thymus ● Derived from the third branchial (pharyngeal) pouch. ● Moves caudally and ends up in the superior mediastinum, just above the heart. ● At birth - the thymus weighs 10-35 kg. And subsequently increases its size in childhood. It attains its maximum weight (30-50 g) at puberty. ● Thymus involutes in individuals who are subjected to severe stress, serious illness, or ionizing radiation. ● Thymus is the central lymphoid tissue that is tasked to transform T stem cells into mature, immunologically competent, and self-tolerant albeit naïve, T stem cells. ● It also needs to produce cytokinesis that regulates T-cell proliferation, maturation, and function in the thymus and other lymphoid tissues and organs ● T lymphocytes are lymphocytes that populate the thymus. ● The cells of the T-cell lineage are often referred to as thymocytes. The adult thymus is composed of two pyramidal lobes fused. Histologic Organization of the Lymph Node ● Each of the two lobes of the thymus is enclosed by a capsule , a dense irregular connective tissue. ● Trabeculae from the capsule divide the lobes, albeit incompletely into lobules of unequal sizes while thin strands of connective tissue from the trabeculae form secondary septa within the gland. ● In routine LM preparation: a thymic lobule exhibits a peripheral, darker-staining region (cortex) that surrounds a central, lighter-staining region (medulla). The trabeculae separating the lobules do not extend deep enough to separate the medulla of adjacent lobules; thus, the medulla of adjacent lobules interconnect. ● Epitheloid cells (epithelial reticular cells) are stellate cells which the stroma of the thymic lobules consists of. They are likewise responsible for producing most of the thymic cytokines, although thymocytes also produce cytokines. ● In the cortex, epitheloid cells (nurse cells) envelop multiple young lymphocytes. The nurse cells promote the proliferation and differentiation of lymphocytes. New T stem cells that arrive from the myeloid tissue settle in the peripheral part of the outer cortex where they transform into lymphoblasts and proliferate. As they mature, they move towards the medulla while progressively becoming smaller such that when they reach the medulla, they are mostly small lymphocytes. During their stay in the cortex, T-cells acquire their receptors. ● In the medulla, small lymphocytes and macrophages are not as numerous as in the cortex. Among the parenchymal cells in the medulla are APCs known as thymic interdigitating dendritic cells. These cells help in preventing autoimmunity by presenting self-antigens to enable T-cells
Histology Lecture
BSMT 2-B | PRE-FINAL TOPIC | SEM 1 2022 - 2023
● There are 500 to 600 lymph nodes in the body. They are interposed along the course of lymphatic vessels. They vary in size ( pinhead to 3 cm in diameter ) depending on their location and the state of activity of the lymphocytes within the organ. ● Lymph nodes are important sites for producing the lymphocytes needed in mounting an immune response. In these organs, activated B and T-cells can proliferate and differentiate into various functional types. ● Lymph nodes are strategically situated in various parts of the body. They are present in the popliteal, inguinal, and axillary regions ; along the sides of the neck ; along the abdominal vessels ; in the mesentery ; and in many other sites. The pattern of their distribution ensures that all the lymph throughout the body passes through several lymph nodes before reaching the major lymphatic vessels (i.e., thoracic duct and right lymphatic duct ). ● Lymph nodes may become swollen and tender when an infection is present in their "Area of jurisdiction." ● Exhibits an indented area called hilus. It is at this area where efferent lymphatic vessels leave , and blood vessels enter and exit the organ. ➔ Afferent lymphatic vessels enter the lymph node on its convex surface. Histologic Organization of the Lymph Node ● Enclosed by a capsule, a dense irregular connective tissue. The capsule gives off the trabeculae that incompletely subdivide the organ into compartments, whose stroma is formed by reticular tissue. ● The parenchyma of the lymph node is divided into a peripheral-located cortex that encloses a centrally located medulla. It consists mainly of lymphocytes, but macrophages, plasma cells, and DCs also abound. ● The boundary between the cortex and medulla is indistinct. It is arbitrarily delineated by the tips of the trabeculae. ● In the cortex, the outer region (outer cortex) is mostly occupied by lymphoid nodules that are embedded in dense lymphoid tissue. The inner region (inner cortex) has no lymphoid nodules and consists simply of dense lymphoid tissue. ● The DCs in B-cell-rich areas (outer cortex) are called follicular dendritic cells. ● They have large, pale nuclei and indistinct borders. Their numerous processes ( dendrites) are joined with those of other dendritic cells by desmosomes. The DCs in T-cell-rich areas (deep cortex), on the other hand, are called interdigitating dendritic cells. They exhibit polymorphic nuclei and processes that interdigitate. ● The medulla is paler staining than the cortex. It is made up of dense lymphoid tissue arranged to form strands called medullary cords , in between which are medullary sinuses Lymphatic Vessels of the Lymph Node ● As they approach the lymph node, afferent lymphatic vessels ramify and give rise to smaller branches that enter the node on its convex surface. The afferent lymphatic vessels are provided with one-way valves that prevent the backflow of lymph. ● They penetrate the capsule of the lymph node and become continuous with the subcapsular sinuses that lie immediately underneath the capsule. The subcapsular sinuses, on the other hand, continue into the trabecular (cortical) sinuses that travel
Histology Lecture
BSMT 2-B | PRE-FINAL TOPIC | SEM 1 2022 - 2023
inward along the trabeculae. ● The trabecular sinuses , in turn, carry on into the bigger medullary sinuses in between the medullary cords. The medullary sinuses unite as they approach the hilus to form several efferent lymphatic vessels. These vessels penetrate the capsule and leave the lymph node at the hilus. ● The sinuses are irregularly shaped lymphatic vessels. Their walls which permit all the constituents of lymph to pass freely consist simply of an endothelium. The endothelial ● cells also serve as APCs and thus, they have limited capacity to engulf particulate matter. ● Associated with the endothelium of the sinuses are numerous macrophages. ● The efferent lymphatic vessels are fewer but bigger than the afferent lymphatic vessels. ● Like the afferent lymphatic vessels, they are also provided with one-way valves which ensure that the lymph that leaves the lymph node does not flow back in. ● Thus, lymph enters a lymph node via its afferent lymphatic vessels. It then passes through the sinuses for filtering (via phagocytosis) by the e macrophages, endothelial cells, and other APCs before draining out of the organ via the efferent lymphatic vessels Blood vessels of the Lymph Node ● The artery that supplies a lymph node enters the organ at the hilus where it breaks up into branches that travel within the trabeculae into the medullary cords. Here, they give off capillaries to supply the medulla. The main arterial branches then proceed to the cortex to form capillary plexuses around the lymphoid nodules. ● The capillaries supplying the cortex drain into venules (post-capillary venules) that travel inwards into the medulla to unite with the medullary venules. Then they form larger vessels that travel with the arteries in the trabeculae. The veins ultimately leave the node at the hilus. ● Lymphocytes enter the lymph node primarily from the blood by passing through the endothelial lining of the blood vessels in T-cell-rich areas. This ensures interaction between B and T-cells. ● The lymphocytes leave the lymph node to join the recirculating pool primarily via
the efferent lymphatic vessels.
Spleen ● Largest lymphoid organ of the body (7 cm x 12 cm) ● Soft and movable structure. Located on the left upper quadrant of the abdominal cavity posterior to the upper part of the stomach ● Medial surface has a notch, the hilus - where blood vessels enter and leave the organ ● Important component of the body’s immune system - the lymphocytes when activated by blood-borne antigens, proliferate and differentiate into different functional types.
Histology Lecture
BSMT 2-B | PRE-FINAL TOPIC | SEM 1 2022 - 2023
central artery terminates and gives off branches (penicillar arteries, penicilli, arteries of the red pulp ) ➔ Penicillar artery - an arteriole but atypical because endothelial cells are cuboidal ➔ It terminated by giving off 2 to 3 sheathed arteries ● Blood from sheathed arteries drains into splenic sinusoids - termed as “open circulation” - blood from arteries flows out in the interstitial spaces then percolates in the sinusoids. ➔ Sinusoids interconnect extensively ➔ Have large regular lumens ( up to 40 μm ) and very thin walls that do not have smooth muscle fibers ➔ Endothelium is atypical ➔ Endothelial cells are fusiform and are capable of limited phagocytosis ➔ Ends are in contact with one another and occasionally form junctions ➔ However, there are gaps in lateral surfaces; rest on a discontinuous basal lamina ➔ There are numerous macrophages ( perisinusoidal macrophage ) - external to the endothelial cells - responsible for filtering of blood that occurs in the spleen ➔ It has processes that extend in the lumen of sinusoids - help the macrophages phagocytose particulate materials in sinusoids ● From sinusoids, blood flows into collecting veins in the red pulp. ● These drain in trabeculae veins which unite to form the splenic vein that leaves the spleen at the hilus Lymph Vessels of the Spleen ● Spleen - has no afferent lymphatic vessels but has efferent vessels ● It starts as blind capillaries - unites to form bigger vessels that follow veins. Mucosa-Associated Lymphoid Tissue ● Refer to the enormous amount of lymphoid tissue that exists in the mucosa and submucosa of the gastrointestinal, respiratory , and genitourinary tracts. ● MALT associated with the gastrointestinal tract is often referred to as gut-associated lymphoid tissue (GALT) while the associated with the trachea and bronchi is sometimes called bronchus-associated lymphoid tissue (BALT). ● In most mucosal surfaces, the Mucosa-associated Lymphoid Tissue consists simply of looser or dense diffuse lymphoid tissue that may contain an occasional solitary lymph nodule. ● In certain area of the body, however, the Mucosa-associated Lymphoid Tissue form larger collections of lymphoid tissue that feature aggregates of lymphoid nodules. ● Notable areas where aggregates of lymphoid nodules embedded in dense lymphoid tissue exist are the colon , vermiform appendix ,
Histology Lecture
BSMT 2-B | PRE-FINAL TOPIC | SEM 1 2022 - 2023
ileum , (where the aggregates are referred to as Peyer’s patches ), and the entrance to the respiratory and digestion tracts where the lymphoid tissue aggregates are called tonsils. ● The larger aggregates of Mucosa-associated Lymphoid Tissue are not, or only partially, enveloped by a capsule. ● They consist of T-cell-rich areas (diffuse lymphoid tissue) and B-cell-rich areas (lymphoid nodules). They also contain numerous APCs. In addition, MALTs are also important sites for generating the lymphocytes that are needed in mounting an immune response. Tonsils ● Form a ring ( Waldeyer’s ring ) underneath the epithelium (in entrances of respiratory and digestive passages) ● They consist of paired palatine tonsils, lingual tonsils and tubal tonsils, and an unpaired pharyngeal tonsil. ● Most are partially encapsulated by dense irregular connective tissue capsules ● In lymphoid nodules of tonsils, lymphocytes are usually abundant on the epithelial side
PALATINE TONSILS
● Located in the lateral aspect, one on each side of the oropharynx ● Each is an ovoid body lodged in between the palatoglossal fold anteriorly and the palatopharyngeal fold posteriorly ● Superficial surface is covered by nonkeratinized stratified squamous epithelium - it forms deep, branching invagination - called tonsilar crypts ● Tonsilar crypts often contain dead epithelial cells, lymphocytes, and other cells that have reached the surface by passing through epithelium LINGUAL TONSILS ● Consists of several discrete masses located in the dorsum of the posterior tongue ● Each has a diameter of 2 to 3 mm ● Superficial surface - covered with nonkeratinized stratified squamous epithelium ● Epithelium ha a single broad deep crypt into which ducts of mucus-secreting glands open.
