Review of the Immune System

• The immune system is made up of billions of individual cells spread throughout the body, which are able to recognize signs of danger and infection.

• An immune cell must sense foreign molecules (antigens) which are only found on infectious microbes, diseased cells, or other foreign sources, in order to be activated

• Immune cells must receive multiple, distinct, signals from other cells (co-stimulatory signals).

  • These signals confirm the presence of a threat and help prevent trigger-happy immune cells from causing damage in the case of a false alarm.

• B and T lymphocytes each recognize only one specific antigent (cognate antigen)

  • B cells produce antibodies that can neutralize infectious microbes

    • B cells can recognize their cognate antigens without help from other cells, but many B cells need help from T cells to become fully activated.

    • B cells present their antigen to helper T cells that are specific for the same antigen, activate the helpter T cell which in turn fully activates the B cell

  • T cells recognize and kill infected or cancerous self cells

    • Antigen Presentation: the process where T cells can only recognize their cognate antigen when they’re bound to surface proteins on other cells

• Although the reliance on other cells for immune activation helps prevent inappropriate immune reactions, this poses a potential challenge.

Importance of the Lymphatic System

• The lymphatic system includes the primary organs and tissues that make up the immune system.

• This system assists in allowing specific immune cells to meet and provide each other the stimulation they require in order to carry out their respective roles in defense.

• It also helps the cells in meeting up quickly enough to protect the body from being overrun with infectious invaders.

Quick Summary of Lymphatic System

• Every tissue in the body is bathed in fluid called lymph, which contains cellular waste product, dead cell debris, and potential pathogens.

• Lymph is pushed through lymphatic vessels into tiny, bean-shaped organs called lymph nodes.

• Humans have hundreds of lymph nodes deposited all over the body.

  • These nodes act as strategic outposts where immune cells can meet and gives each other the activating and costimulatory signals necessary to launch an immune attack.

Lymph Nodes Overview

• Each lymph node is surrounded by a protective layer of connective tissue called the capsule

• Lymph arrives to the node in afferent lymphatic vessels, then enters the sinuses which are channels that allow lymph to flow through the different compartments of the node.

• Lymph nodes sinuses are lined with macrophages and dendritic cells that sample lymph for pathogens and debris that could trigger an immune reaction

  • Macrophages in the sinuses are like flypaper in the lymph node; they trap lymph-borne pathogens and prevent them from infecting other cells in the node

Lymph Nodes Organization

• The ability of the lymph nodes in coordinating immune response comes from their organization.

• Each lymph node has specific compartments for distinct cell types, largely defined by chemokines

  • These chemokines allows for lymphocytes to find their cognate antigens and interact with other cells in ways that launch an immune response

• Closest to the capsule is the outer cortex of the lymph node (the B cell zone), which is made up of spherical structures or follicles that are full of B cells

• Moving deeper into the node is the T cell zone, which is full of T cells

  • Dendritic cells migrate to the T cell zone of lymph nodes when they become activated

  • These cells have been sampling bits of microbes or cellular debris throughout the body

  • Dendritic cellls present antigens to the T cells in the lymph node, looking for the T cell that matches the antigen

• Helper T cells tend to live along the margin between the B and T cell zone

  • This is so that they can find the B cell that shares its cognate antigen and give rise to germinal centers (sites of B cell activation and division)

• Naive lymphocytes (B and T cells that haven’t been activated yet) drain from the blood into the lymph nodes

  • There they circulate through their respective zones, quickly looking for cells presenting their cognate antigens

  • If they don’t find it, they move from lymph node to lymph node, eventually circling back to the bloodstream

  • If they found their cognate antigens and receive the proper costimulation (1), the lymphocytes becomes activated (2), divides rapidly (3) and migrates to the site of trouble to fight the threat (4)

Components of the Lymphatic System

• Lymph nodes and lymphatic vessels are the main structures comprising the lymphatic system, but they aren’t the only ones involved in immune organization and defense.

• Other structures include the spleen, the thymus, and mucosa-associated lymphoid tissues.

Description of the Spleen

• Spleen: the largest lymphatic organ in the body with a dark reddish-purple color; it’s situated behind the stomach and has two main functions:

  • It removes old red blood cells from circulation which occurs in a region of the spleen known as the red pulp

  • It filter pathogens and immune complexes from the blood which occurs in region called the white pulp

• The spleen only filters blood, not lymph, unlik lymph nodes; it also holds an important reserve of blood, platelets, and monocytes.

• The red pulp makes up about 75% of the spleen’s volume and is comprised of the Cords of Billroth and venous sinus.

  • Cord of Billroth (splenic cords) are lined with connective tissue and fibroblasts, they’re also full of macrophages

Process of the Red Pulp

• Splenic blood enters “open circulation” in the cords, so the blood isn’t flowing through endothelial-lined vessels and old/damaged red blood cells can be eaten by red pulp macrophages.

• To re-enter circulation, red blood cells must enter the venous sinuses by passing through the interendothelial slit.

  • The slit is a narrow passageway between endothelia cells that only healthy, flexible red blood cells can fit through.

  • Old/damaged blood cells that cannot fit through the slit remain trapped in the red pulp where macrophages and dendritic cells disposed of them

• Microbes and infected red blood cells coated with antibodies are also detroyed by macrophages in the red pulp

• This process of infiltration allows the spleen to remove old blood cells from the circulation and also enables the recycling of iron from old red blood cells to be used in new ones

• Interspersed within the red pulp are pockets of white pup which have a similar structure to the lymph nodes, with T cell zones and B cell follicles

Process of the White Pulp

• In the spleen the T cell zone surrounds the arterioles and is located in the periarteriolar, the lymphoid sheath (PALs)

• Outside the sheath are the B cell follicles which are surrounded by the marginal zone

• Macrophages and dendritic cells in the marginal zone can help filter circulating antigens, blood-borne pathogens, and cells or particles coated in antibodies (antigen antibody complexes)

  • The marginal zone also contains special noncirculating B cells called marginal zone B which do not require T cell help for activation, really affective amongst first response

• These marginal zone do not require T cell for activation and are effective first responders at sensing and neutralizing blood-borne threats that appear at the marginal zone.

Description of the Thymus

• Unlike the lymph nodes and the spleen, which enable immune response by coordinating interactions between lymphocytes and antigen-preseting cells, the thymus is the site of early T cells development

  • In humans, it is positioned right above the heart and it’s the biggest and most active during infancy and childhood

• T cell progenitors migrate from the bone marrow to the thymus, where thymic stromal and epithelial cells guide their development

• The thymus has distinct regions, which are known as the cortex and the medulla, each corresponds to different stages of T development

  • Less mature cells can be found in the cortex, and more mature cells are found in the medulla.

• Naive T cells leave the thymus to circulate through the bloodstream and lymph nodes once fully developed

Mucosa-Associated Lymphoid Tissue (MALT)

• A all encompassing term for several different regions of lymphatic tissue.

  • Mucosa surfaces include the digestive tract, airways, the urogenital tract, salivary glands, lactating breasts, conjunctivae and lachrymal glands of eyes

  • MALT is also found in the tonsils, adenoids and appendix.

• Mucosal surfaces are thin and permeable, often lined by just a single layer of epithelial cells.

  • This is important because mucosal surfaces facilitate interactions with the surroundings.

  • Ex. Airway epithelium enables gas exchange and the intestinal epithelium absorbs nutrients.

• This thin barrier also renders mucosal surfaces particularly susceptible to infection

  • To counter the increased risk of infection, most mucosal surfaces are equipped with MALT.

  • These are structurally similar to lymph nodes, with B cell follicles and T cell zones, but they have specialized features depedning on tissue type

  • Ex. Gut-associated lymphoid tissue (GALT) in the intestine is supplied with antigens from special cells called microfold or M cells

    • M cells continuously sample antigen from the intestinal lumen and transfer it to the Peyer’s patches (type of GALT in small intestine)

    • M cells in nasal-associated (NALT) and bronchus-associated (BALT) catch inhaled microbes and microbes trapped in mucus, making them available for digestion and antigen presentation by dendritic cells

• Mucosal surfaces are often controlled by activated lymphocytes, even in the absence of infection

• MALT is also uniquely effective at regulating immune responses.

  • Regulatory responses in the mucosa are constantly at play to help prevent constant immune activation in response to harmless antigents

  • These antigents include bacteria, food, and other particles that pass through mucosal surfaces and shouln’t trigger an immune response

• B cells at mucosal sitens produce a specific class of antibody (IgA) that is good at preventing bacteria from crossing the epithelial barrier without inducing an immune response

• These mechanisms work together to keep the mucosal barrier surfaces resistant to infection without requiring an overactive immune response.