I paʻa ke kino o ke keiki i ka lāʻau.

That the body of the child be solidly built by the medicines.

A mother ate herbs during pregnancy and nursing for the sake of the baby’s health. The herbs were given to the child up to the age of twenty so that he would be healthy and strong through maturity and old age.

ʻŌlelo Noʻeau, compiled by Mary Kawena Pukui, #1252

Introduction

Figure 22.1: Kealakekua Bay and the Village Kowroaa: Kaʻawaloa in 1779 by John Webber, artist aboard Cook’s ship

The function of the immune system is to resist disease development. The immune system works by recognizing (binding) and destroying molecules that are foreign (different from your own). Sometimes your own body cells become damaged and are recognized as abnormal and destroyed. In the case of autoimmune disease, components of your immune system bind and attack healthy tissues. Generally speaking, the immune system slowly evolves to resist diseases that are in the surrounding environment.  It may be unprepared, however, to deal with new foreign threats. When geographically isolated peoples come into contact, such as when Captain Cook and his crew first arrived in the Hawaiian Islands, the immune systems of each respective group often aren’t able to resist the pathogens carried by the other. In such situations, diseases may spread quickly, often with devastating consequences.

22.1 Types of Pathogens

Figure 22.2: Relative Size of Viruses and Bacteria (OpenStax Microbiology)

Pathogens are biological agents that cause disease (abnormal tissue/ organ function).  There are many different types of pathogens. Some pathogens, such as bacteria, are prokaryotic and structurally very different from your eukaryotic cells. These are easier to be recognized by your immune system as a foreign threat. Other pathogens may be eukaryotic,  appearing more similar to your own cells and generally harder to recognize as foreign. The greater the molecular differences between your cells and a pathogen, the more likely the immune system will be able to bind and destroy it. Size can make a difference too, as larger molecules are more likely to be recognized than smaller ones.

Bacteria are living, prokaryotic microbes usually with lipopolysaccharide or peptidoglycan components in the cell walls. These large molecules have structural patterns absent from human cells and therefore are usually easily recognized by the immune system. If not stopped, some bacteria may adhere to the body and multiply using your body as a food source. Many bacteria also produce and secrete toxins that may contribute to disease symptoms.

Viruses are non-living but can still be pathogens.  Due to their implications for health and disease, virology is often covered in introductory microbiology courses. Viruses are simply relatively small strands of DNA or RNA wrapped in protein. Because viruses are non-living, they require living cells to propagate, which often causes pathology in the process. Even though they are much smaller than bacteria and replicate inside living cells, viruses have unique molecular (protein, DNA, or RNA) patterns that our immune system is able to recognize as foreign.

Fungi are eukaryotic organisms and some species are pathogens. Even though they consist of eukaryotic cells, fungi often contain cell wall components such as chitin and glucans that are dissimilar to any human molecule, thus allowing for recognition.

Protists and worms are other examples of potential eukaryotic human pathogens. Protists are a group of single celled microorganisms whereas worms are multicellular.  Both include species known to be parasitic pathogens. The diverse prokaryotic domain archaea contains no known human pathogens, nor does the multicellular eukaryotic plant kingdom aside from potential toxicity.  Viroids, a virus-like nucleic acid but without a protein coat, are only known to cause disease in plants. Whether a living microbe or not, all the above contain nucleic acids (DNA and/or RNA). Prions are proteins capable of causing disease directly.  Proteins have a specific three dimensional shape that determines its function.  Prion proteins take on an altered shape and, upon contact, cause normally shaped proteins to do the same.  These misfolded proteins build up in cells causing disease.

Not all microbes are pathogenic! Your skin and mucous membranes are covered in microbes that don’t cause disease. The microbiota include bacteria, fungi, viruses among others and prevent disease by outcompeting pathogens for nutrients. Normal flora can vary between people with different diets, lifestyles and living environments.  In addition, different areas of the body house different microbe populations. Using normal flora microbes as a method for treating disease is a growing area of medical research.

How does the immune system “recognize” foreign molecules? As we previously learned in the hematology chapter, cells of the immune system are called leukocytes (leuko = white, cyte = cells, aka white blood cells, WBCs). Leukocytes have receptors that bind foreign molecules triggering the release of antimicrobial peptides (AMPs), digestive enzymes and/or cytokines. Cytokines stimulate other cells to facilitate and amplify the immune response. Just like RBCs, all WBCs are produced in the bone marrow. From there, leukocytes may travel to reside in the peripheral tissues or circulate the body via the cardiovascular and lymphatic systems.

22.2 Lymphatic System

The function of the lymphatic system is to concentrate and screen interstitial fluid for pathogens in areas of your body most likely to get infected. Plasma that leaves the cardiovascular system and enters the tissues becomes interstitial fluid (IF, inter = between, stitial = tissues). Most of that fluid returns to the cardiovascular system at the venous end of capillary beds. However, about 20% of the remaining IF enters lymphatic capillaries as lymph (fluid of the lymphatic system).

Figure 22.6: Lymphatic Capillaries Lymphatic capillaries are interlaced with the arterioles and venules of the cardiovascular system. Collagen fibers anchor a lymphatic capillary in the tissue (inset). Interstitial fluid slips through spaces between the overlapping endothelial cells that compose the lymphatic capillary.

Precapillary Sphincters and Valves: (a) Precapillary sphincters are rings of smooth muscle that regulate the flow of blood through capillaries; they help control the location of blood flow to where it is needed. (b) Valves in the veins prevent blood from moving backward. (credit a: modification of work by NCI) (OpenStax Biology 2e)	Lymph Capillaries in the Tissue Spaces: Fluid from the capillaries moves into the interstitial space and lymph capillaries by diffusion down a pressure gradient and also by osmosis. Out of 7,200 liters of fluid pumped by the average heart in a day, over 1,500 liters is filtered. (credit: modification of work by NCI, NIH) (OpenStax Biology 2e)
Capillary Exchange Net filtration occurs near the arterial end of the capillary since capillary hydrostatic pressure (CHP) is greater than blood colloidal osmotic pressure (BCOP). There is no net movement of fluid near the midpoint since CHP = BCOP. Net reabsorption occurs near the venous end since BCOP is greater than CHP.

Figure 22.7: Lymph Capillaries and Pressure gradient

Lymphatic capillaries are low-pressure single-cell thick vessels that avoid collapsing by anchoring filaments. Lymph enters mini flaps, slits in between adjacent cells. Similar to how blood moves in veins, lymph moves in the direction of the heart due to a pressure gradient difference caused by the respiratory pump and the prevention of backflow by lymphatic valves. In addition, pulsatile movement of blood in adjacent arteries and smooth muscles of larger lymphatic vessels prevents lymph stagnation. Lymphatic capillaries combine to form the larger lymphatic vessels. Lymphatic vessels deliver lymph to lymph nodes.

Location, Structure, and Histology of the Thymus The thymus lies above the heart. The trabeculae and lobules, including the darkly staining cortex and the lighter staining medulla of each lobule, are clearly visible in the light micrograph of the thymus of a newborn. LM × 100. (Micrograph provided by the Regents of the University of Michigan Medical School © 2012)
Major Trunks and Ducts of the Lymphatic System The thoracic duct drains a much larger portion of the body than does the right lymphatic duct.
Structure and Histology of a Lymph Node Lymph nodes are masses of lymphatic tissue located along the larger lymph vessels. The micrograph of the lymph nodes shows a germinal center, which consists of rapidly dividing B cells surrounded by a layer of T cells and other accessory cells. LM × 128. (Micrograph provided by the Regents of the University of Michigan Medical School © 2012)	Mucosa-associated Lymphoid Tissue (MALT) Nodule LM × 40. (Micrograph provided by the Regents of the University of Michigan Medical School © 2012)

Figure 22.8: Lymph Nodes, Lymphatic Trunks and Ducts

Lymph nodes house many leukocytes that bind foreign particles present in the lymph and initiate an immune response. The node is divided into medullary and cortical regions contained by an outer fibrous capsule which extends inward forming trabeculae. These divide the cortex into several lobules. Lymph enters lymph nodes through afferent lymphatic vessels on the convex side and exits via efferent lymphatic vessels at the hilum.

Figure 22.9: Lymphatic System Trunks: Terminal collecting trunks of right side. a. Jugular trunk. b. Subclavian trunk. c. Bronchomediastinal trunk. d. Right lymphatic trunk. e. Gland of internal mammary chain. f. Gland of deep cervical chain.

As lymph moves toward the heart, lymphatic vessels combine to make bigger lymphatic trunks, and trunks eventually fuse to form the larger lymphatic ducts. There are only two lymphatic ducts. The right lymphatic duct returns lymph from the upper right quadrant of the body to the cardiovascular system at the junction of the right subclavian and right internal jugular veins. The thoracic duct returns lymph from the rest of the body at the left subclavian — left jugular vein junction.

Figure 22.10 (a) Red bone marrow can be found in the head of the femur (thighbone) and is also present in the flat bones of the body, such as the ilium and the scapula. (b) Red bone marrow is the site of production and differentiation of many formed elements of blood, including leukocytes. (c) The thymus is a bi-lobed, H-shaped glandular organ that is located just above the heart. It is surrounded by a fibrous capsule of connective tissue. The darkly staining cortex and the lighter staining medulla of individual lobules are clearly visible in the light micrograph.

The bone marrow and the thymus are considered the primary lymphoid organs because they are involved in leukocyte development. Secondary lymphoid organs (lymph nodes) house mature leukocytes to facilitate activation of the immune system. Lymph nodes are found in areas of the body that are at high risk for invading bacteria such as the axillary, inguinal, and cervical areas.

Figure 22.11: The spleen is similar to a lymph node but is much larger and filters blood instead of lymph. Blood enters the spleen through arteries and exits through veins. The spleen contains two types of tissue: red pulp and white pulp. Red pulp consists of cavities that store blood. Within the red pulp, damaged red blood cells are removed and replaced by new ones. White pulp is rich in lymphocytes that remove antigen-coated bacteria from the blood.

Though the spleen is primarily responsible for filtering blood, not lymph, it is often considered the body’s largest lymph node. It has a similar organization as other lymph nodes. Between trabeculae, red pulp areas are where damaged RBCs are broken down and white pulp areas contain leukocytes performing more typical lymph node functions.

Figure 22.12: Mucosa-associated Lymphoid Tissue (MALT) Nodule LM Å~ 40. (Micrograph provided by the Regents of the University of Michigan Medical School ˝ 2012)

Other specialized lymph nodes are associated with the oral cavity (tonsils) and the digestive system (Peyer’s patches and MALT= mucosa-associated lymphoid tissue). Part of the MALT is the bronchus-associated lymphoid tissue (BALT) which is the lymphoid nodules associated with the respiratory tract. Lacteals are the specialized lymphatic capillaries associated with the gut. Lacteals absorb bile and lipids from the digestive tract. This fluid is called chyle (lymph and chyme) and has a milky appearance quite distinct from regular lymph. It drains into the cisterna chyli (the swollen inferior end of the thoracic duct).

22.3 Innate Immunity

Innate immunity refers to the anatomical structures and physiological processes in place at birth that provide resistance to pathogens entering, binding, and causing disease to the body. These innate mechanisms of disease resistance can be divided into the first and second lines of defense.

Figure 22.13: Innate Immune System Table: The innate immune system is made up of physical barriers and internal defenses.

Figure 22.14: Phagocytic cells contain pattern recognition receptors (PRRs) capable of recognizing various pathogen-associated molecular patterns (PAMPs). These PRRs can be found on the plasma membrane or in internal phagosomes. When a PRR recognizes a PAMP, it sends a signal to the nucleus that activates genes involved in phagocytosis, cellular proliferation, production and secretion of antiviral interferons and proinflammatory cytokines, and enhanced intracellular killing.

The first line of defense includes barriers such as your skin and mucous membranes that are physically difficult to cross. These boundaries contain chemical substances that resist pathogen adherence and propagation. For instance, sweat, tears, and saliva are acidic and contain antimicrobial peptides. The first line of defense barriers may become compromised due to injury or other conditions. In these cases, the second line of defense mechanisms comes into play. The cells of innate immunity contain receptors that bind certain patterns common among pathogens but are drastically different from those found on human cells.  PAMPs (pathogen-associated molecular patterns) are those molecular patterns on pathogens your innate immune system can recognize. Your tissues that have become damaged through injury may also elicit molecular patterns (DAMPs, damage-associated molecular patterns) that your innate immune cell receptors can bind. In either case, the receptors on innate immune cells that bind PAMPs and DAMPs are called PRRs (pattern recognition receptors).

PAMPs include the bacterial macromolecules lipopolysaccharide (LPS) and peptidoglycan. Some viruses and bacteria contain unique DNA and RNA sequences that can be recognized by PRRs. Fungal pathogens can be recognized by PRRs specific for the PAMPs on glucan and chitin. Innate immune cells with PRRs can be divided into two major classes: the granulocytes (cells with granules) and agranulocytes (cells without granules).

Cells of Innate Immunity

Figure 22.15: Granular Leukocytes. A neutrophil has small granules that stain light lilac and a nucleus with two to five lobes. An eosinophil’s granules are slightly larger and stain reddish-orange, and its nucleus has two to three lobes. A basophil has large granules that stain dark blue to purple and a two-lobed nucleus.

Figure 22.16: An APC, such as a macrophage, engulfs and digests a foreign bacterium. An antigen from the bacterium is presented on the cell surface in conjunction with an MHC molecule. Lymphocytes of the adaptive immune response become activated when they bind the MHC embedded foreign molecules.

Since they have multilobed nuclei of various shapes, granulocytes are also known as polymorphonuclear cells (PMNs). There are three types of granulocytes. Neutrophils are the most abundant of all the leukocytes. They are also typically the first responders to a site of infection. When their PRRs bind a PAMP, the membrane can wrap around and engulf the pathogen in a process known as phagocytosis. Once the pathogen is internalized, it is broken down by digestive enzymes released from cytoplasmic granules. Neutrophils may also release chromatin forming neutrophil extracellular traps (NETs) that help prevent the spread of pathogens. Neutrophils are destroyed in the process, therefore these cells have a high turnover rate, typically lasting only 10 days or so.  Eosinophils have PRRs and granule enzymes for attacking certain parasites. Basophils (and the similar mast cells) reside in the peripheral tissues of adjacent mucous membranes and contain granules with histamine and other inflammatory molecules. Both eosinophils and basophils are among the least abundant leukocytes and often implicated in allergic reactions.

Figure 22.17: Natural killer (NK) cells are inhibited by the presence of the major histocompatibility cell (MHC) receptor on healthy cells.  Cancer cells and virus-infected cells have reduced expression of MHC and increased expression of activating molecules. When a NK cell recognizes decreased MHC and increased activating molecules, it will kill the abnormal cell.

Agranular cells of innate immunity include macrophages (macro = big, phage = to eat), dendritic and natural killer cells (NK). Originating as blood monocytes, macrophages and dendritic cells are phagocytes like neutrophils. However, macrophages and dendritic cells activate cells of the adaptive immune system in a process called antigen presentation. Therefore, these cells are known as APCs (antigen presentation cells) and act as a bridge to the body’s more evolutionary advanced adaptive immune defenses. Part of the lymphocyte lineage, NK cells are primarily responsible for monitoring your own cells. NK cells release perforins and granzymes to destroy damaged or irregular cells.  Perforins, make a hole (perforate) in cell membranes and granzymes are proteases that induce target cell apoptosis.

Figure 22.18: Innate immune system cells. The characteristics and location of cells involved in the innate immune system are described. (credit: modification of work by NIH)

Inflammation

Figure 22.19: Acute Inflammation: Resident leukocytes and damaged cells release histamine and other inflammatory chemicals in response to infection or injury. The increased blood flow brings fluid, proteins, phagocytes, and other immune cells to enter infected tissue. These events result in swelling, reddening and pain around the injured site.

What is the innate immune response to a puncture wound, such as a cut with a dirty knife? Your first line of defense, physical and chemical barriers, have been compromised and now you must rely on the second line of defense mechanisms to stop pathogens from growing in your body. How are cells of the innate immune system called to the site of injury? What damage control mechanisms occur to allow the body time to heal?  The answer to both these questions is inflammation; one of the hallmarks of innate immunity. If you’ve ever experienced acute inflammation before, you may easily recognize the cardinal signs: redness, heat, swelling, and ʻeha (pain). Some consider loss of function or impaired function to be the fifth cardinal sign.  Words ending with the suffix -itis are used to describe inflammation of specific organs and tissues. For example, dermatitis refers to inflammation of the skin (dermis) and pericarditis refers to inflammation of the pericardium around the heart.

The four phases of inflammation are:

1. Tissue injury causing inflammatory chemical release
2. Vasodilation
3. Increased vascular permeability
4. Phagocyte mobilization

It is important to note that inflammation in response to tissue injury and/or infection is the first step towards healing. Benefits of the localized acute inflammatory response include:

1. Impeding the spread of pathogens
2. Destroying pathogens
3. Removing debris and damaged tissue
4. Repairing tissue
5. Activating additional immune defenses

Figure 22.20: Interferons are cytokines released by a cell infected with a virus. Interferon-α and interferon-β signal uninfected neighboring cells to inhibit mRNA synthesis, destroy RNA, and reduce protein synthesis (top arrow). Interferon-α and interferon-β also promote apoptosis in cells infected with the virus (middle arrow). Interferon-γ alerts neighboring immune cells to an attack (bottom arrow). Although interferons do not cure the cell releasing them or other infected cells, which will soon die, their release may prevent additional cells from becoming infected, thus stemming the infection.

Table 22.1: Chemical Defenses of Nonspecific Innate Immunity – Cytokines (OpenStax Microbiology)

Inflammation can be triggered by several factors including physical trauma, intense heat, irritating chemicals, and infection by a pathogen.  As a result of tissue injury, inflammatory chemicals are released into the extracellular fluid to alert the rest of the body that there is a problem and healing is needed. Some of these are cytokines that alert the rest of the immune system, via both short (autocrine and paracrine) and long-distance (endocrine) communication. Common cytokines involved in the inflammatory response include CSFs (colony-stimulating factors), chemokines, interferons, and interleukins. CSFs induce leukopoiesis (leukocyte proliferation in bone marrow), chemokines act as a homing beacon for the site of injury, interferons impede viral production within cells, and interleukins allow one WBC to stimulate others (inter = between, leuk = leukocytes, in = protein). Interferons (INFs) are released by virus-infected cells and bind receptors of other cells, causing them to be more resistant to viral infection. Typically, INFs interfere with viral nucleic acid replication in some way. There are many different types of interferons, INF𝞪, INF𝛃, and INF𝞬 being the most well-known. The INFs secreted by infected cells can also activate other immune cells such as NK cells and macrophages.

Table 22.2: Chemical Defenses of Nonspecific Innate Immunity – Inflammation-eliciting mediators (OpenStax Microbiology)

Other inflammatory chemicals exacerbate the inflammation response itself.  These include histamine, kinins, prostaglandins, and the complement family of plasma proteins. All of these contribute to vasodilation (increase in blood vessel diameter) and promote cell migration to the site of injury. Vasodilation of the local arterioles results in hyperemia (increased blood flow) near the site. Inflammatory mediators also increase the permeability of local vasculature, causing leakage of fluid into the interstitial space, resulting in edema (swelling) and redness. The increase in pressure causes heat and pain in the area. Pain can also be caused by the toxins secreted by invading pathogens or chemicals released by damaged tissues.

The flow of fluid to a site of infection helps to sequester (isolate, to keep separate) pathogens. Protein-rich fluids of the plasma enter the tissues and help move foreign material into the surrounding lymphatic vessels for transport to the lymph nodes. Clotting factors that facilitate wound repair also move into the area.

Complement System

Figure 22.21: The classic pathway for the complement cascade involves the attachment of several initial complement proteins to an antibody-bound pathogen followed by rapid activation and binding of many more complement proteins and the creation of destructive pores in the microbial cell envelope and cell wall. The alternate pathway does not involve antibody activation. Rather, C3 convertase spontaneously breaks down C3. Endogenous regulatory proteins

Complement is a family of proteins that serve to enhance both the innate and adaptive immune responses. The complement system is a cascade of events initiated by either the classical, alternative, or lectin pathways. It begins with several proteins becoming activated by enzymatic fragmentation in the presence of a pathogen. In the classical pathway, complement proteins are activated by the presence of antibodies (immunoglobulin, y-shaped proteins of the adaptive immune system).  The alternate pathway is initiated by a pathogen’s lack of the inhibitory proteins that are present on your cells.  The lectin pathway stimulates the complement cascade when mannose residues are exposed on some bacterial cell walls.  The activated fragments then activate other complement proteins which, in turn, activate others, and so on. Ultimately this process leads to destruction of bacteria, enhanced inflammation and mobilization of leukocytes. Key complement proteins include C3 and C5 which, when activated, produce the fragments C3a, C3b, C5a and C5b. C3a and C5a both increase vascular permeability, smooth muscle construction and mast cell degranulation. C3b is part of the protease that activates C5.  C5b initiates formation of the MAC (membrane attack complex) on the surface of certain target cells by triggering the interaction of C6, C7, C8 and several C9s.  The polymerization of C9 creates a hole in bacterial membranes disrupting the target cell. Additionally, C3b is an opsonin which is a molecule that enhances phagocytosis by binding to the pathogen surface.  Neutrophils and macrophages have C3b receptors allowing them to recognize C3b coated pathogens more readily and initiate phagocytosis.

Fever

Fever, or pyrexia, is an abnormally high body temperature which is part of a normal innate immune response. Pathogens and leukocytes release pyrogens that signal the hypothalamus to raise body temperature. Muscle contractions increase along with the sensation of feeling cold. Secreted prostaglandins enhance the fever-inducing effect. If you’ve ever taken care of a sick keiki (child), you know a high fever can be worrisome. You may have wanted to administer antipyretic (fever-reducing) medications to make them feel more comfortable. Fevers are commonly thought of as undesirable, but in fact, they benefit the body by inhibiting the production of viruses and bacteria, increasing the metabolic rate of your cells (and thus the healing process), and enhancing the actions of immune system proteins such as interferons and some enzymes. Unless it is unusually high, fevers aid in the healing process.

Antimicrobial Peptides

Table 22.3: Antimicrobial Peptides (AMPs) OpenStax Microbiology

There is a large variety of antimicrobial peptides (AMPs) that facilitate the innate immune response. These are chains of 12-50 amino acids that are toxic to certain microbes by disrupting cell membranes or interfering with the synthesis of nucleic acids, proteins or cell wall components.  Some AMPs may block the activity of specific enzymes while others may serve as immunomodulators.  In many cases, specific AMPs bind multiple targets in diverse species such as bacteria, fungi and viruses.  For example, dermcidin and defensins are two chemical classes of AMPs with antibacterial, antifungal and antiviral properties in addition to other functions.  Dermcidin is a protein of over 100 amino acids that is chopped up into smaller mature peptides by sweat proteases.  Defensins have propeptides that must be removed for activation which may occur within or after being secreted out of a cell. For instance, neutrophils store defensins within their granules to facilitate the digestion of phagocytized bacteria.

Phagocyte mobilization

Figure 22.23: Extravasation (Diapedesis) of Leukocytes: Damaged cells and macrophages that have ingested pathogens release cytokines that are proinflammatory and chemotactic for leukocytes. In addition, activation of complement at the site of infection results in production of the chemotactic and proinflammatory C5a. Leukocytes exit the blood vessel and follow the chemoattractant signal of cytokines and C5a to the site of infection. Granulocytes such as neutrophils release chemicals that destroy pathogens. They are also capable of phagocytosis and intracellular killing of bacterial pathogens.

As a result of tissue injury, nearby cells release interleukins, chemokines and CSFs.  Some interleukins and C5a induce endothelial cells to express CAMs (cell adhesion molecules).  CSFs cause leukocytosis (high white blood cell count). Blood cells tend to travel in the middle of vessels where friction is low.  However, when CAMs are present leukocytes stick and roll along the vessel wall, slowing their velocity in a process called margination. During diapedesis, the leukocytes stop completely and squeeze through the clefts between endothelial cells. Chemokines diffusing from the site of injury attract leukocytes via chemotaxis. Neutrophils are the first responders, quickly followed by macrophages.  Remember, neutrophils are phagocytes specialized to destroy microbes and contain infections.  Macrophages, on the other hand, are phagocytes that activate adaptive immunity.

22.4 Adaptive Immunity

Figure 22.24: Antigens may interact with a variety of lymphocyte receptors depending on how many binding motifs (epitopes) are present.

Unlike cells of innate immunity, lymphocytes (T and B cells) each have unique, seemingly random receptors. This enables them to potentially bind any foreign object unrecognizable by PRRs of the innate immune system. Any molecule that can bind a T or B cell receptor is an antigen. Upon binding antigen, lymphocytes respond by secreting interleukins and other molecules to facilitate neutralization of the pathogen. Additionally, the lymphocytes will proliferate in a way to strengthen pathogen recognition over time and establish an immunological memory. Before lymphocytes can perform any of these functions, however, the adaptive immune system must first be activated by APCs.

Major Histocompatibility Complex

Figure 22.25: Major histocompatibility complex (MHC). This figure illustrates the activation of a naive (unactivated) lymphocyte by an antigen-presenting MHC I molecule on an infected body cell. Once activated, perforins and granzymes are released inducing apoptosis in the infected cell.

The major histocompatibility complex (MHC) are two distinct membrane bound proteins (MHC class I and II) that play roles in antigen presentation.  Most cells in your body express MHC class I.  Routinely, your own proteins are digested, pieces of 8-11 amino acids bind MHC-I and are displayed on the cell surface.  However, if any of these cells are infected by intracellular pathogens, pieces of digested pathogen molecules can bind MHC-I instead.  Intracellular pathogens include bacteria, viruses and some multicellular parasites.

Figure 22.26: APBIO MHC-II antigen presentation by APCs.

APCs, such as macrophages and dendritic cells, express MHC-II.  Remember, these cells are phagocytes.  When they engulf and digest pathogens, pieces of the foreign molecules (usually 13-17 amino acids) bind MHC-II and are displayed.  APCs may encounter a pathogen in the peripheral tissues or within the lymphatics. After phagocytosis, the APCs migrate to lymph nodes where helper [pb_glossary id="5260"]T cells (Th)[/pb_glossary] are highly concentrated.  The first and essential step in adaptive immunity activation is when an APC displays antigen to a Th with a receptor that recognizes (binds) the antigen-MHC complex. MHC polygeny ensures any one individual the potential to display a great variety of antigens.  MHC polymorphism greatly increases the variety of presented antigens within a population.  However, true to its name, MHC polymorphism is the main cause of mismatched transplant rejection (major = main cause, histo = tissue, compatibility = donor/ recipient compatible).

T Cells

Table 22.4: Classes of T Cells – OpenStax Microbiology

Table 22.5: Subtypes of Helper T Cells – OpenStax Microbiology

Figure 22.27: Naïve CD4⁺ T cells engage MHC II molecules on antigen-presenting cells (APCs) and become activated. Clones of the activated helper T cell, in turn, activate B cells and CD8⁺ T cells, which become cytotoxic T cells. Cytotoxic T cells kill infected cells.

Helper T cells

Figure 22.28: Helper T Cell: This illustration depicts the activation of a naïve (unactivated) helper T cell by an antigen-presenting cell and the subsequent proliferation and differentiation of the activated T cell into different subtypes.

Th are also known as CD4+ T cells since they express the surface protein CD4.  This and other outer membrane proteins are essential in the activation process.  Once activated, Th cells secrete IL-2 which drives proliferation in an autocrine and paracrine manner.  Depending on the cytokine environment, activated Th cells will promote adaptive immune responses to target either intracellular or extracellular pathogens by stimulating other lymphocytes to become effector T cells and/or effector B cells.  These cells will target pathogens directly.  In some cases, CD4+ T cells become regulatory T cells (Treg, suppressor T cells) that dampen the immune responses of effector cells.

Cell-mediated Immunity

To target intracellular pathogens, cell-mediated immunity is activated by helper T cell subclass Th1. This involves cytotoxic T cells (aka CD8+ T cells, TC) surveying your own tissues looking for unhealthy cells. If cells in your body are cancerous or infected by a virus or other pathogen, MHC-I will display these antigens.  This, along with signals from Th1, activate TC cells to release destructive perforins and granzymes. TC may also express Fas ligand (FasL) which binds Fas on target cells inducing apoptosis.

Humoral Immunity

Figure 22.29: T-independent antigens: T-independent antigens have repeating epitopes that can induce B cell recognition and activation without involvement from T cells. A second signal, such as interaction of TLRs with PAMPs (not shown), is also required for activation of the B cell. Once activated, the B cell proliferates and differentiates into antibody-secreting plasma cells.

Figure 22.30: B Cell Activation: In T cell-dependent activation of B cells, the B cell recognizes and internalizes an antigen and presents it to a helper T cell that is specific to the same antigen. The helper T cell interacts with the antigen presented by the B cell, which activates the T cell and stimulates the release of cytokines that then activate the B cell. Activation of the B cell triggers proliferation and differentiation into B cells and plasma cells.

The second type of adaptive immunity involves Th2 stimulating B cells promoting the secretion of antibodies. When B cells bind antigen and receive IL-4 signals from Th cells they become activated which includes proliferating and differentiating into plasma cells (antibody secreting B cells). Since antibodies are secreted out of the cell into the surrounding body fluid, this type of immunity is called humoral immunity (humors = bodily fluids).  T cell-independent antigens are molecules that can stimulate B cells to differentiate into plasma cells without signals from Th cells.  These are typically very large molecules with multiple, repeating epitopes (the specific region to which a receptor binds).  T cell-independent antigens stimulate B cells by binding multiple BCRs simultaneously or through interactions with other surface proteins (such as the case with bacterial LPS).  However, typically antigens are T cell-dependent antigens.

Antibodies

Figure 22.31: B-cell receptors are embedded in the membranes of B cells. The variable regions of all of the receptors on a single cell bind the same specific antigen.

Antibodies are complex molecules made up of four protein subunits (two heavy chains and two light chains). The Y-shaped protein arms are flexible and contain the antigen-binding regions on the distal ends known as the Fab (fragment of antigen binding, aka the variable region). This amino acid sequence varies greatly in this area such that there is a high likelihood for some antibodies to bind foreign antigens.  The base of the protein, called the Fc region, contains the functional domain. This part helps activate complement and phagocytosis. Fc stands for “fragment of crystallization” since this protein fragment crystallizes after protein digestion. It may help to associate the “c” in Fc with the word “constant”, however, since this portion is referred to as the constant region..

Table 22.6: Table of Antibody Isotypes: IgD is bound to the membrane as the B cell receptor.  All other isotypes are secreted forms.

Figure 22.32: Secondary antibody response: Compared to the primary response, the secondary antibody response occurs more quickly and produces antibody levels that are higher and more sustained. The secondary response mostly involves IgG.

There are 5 distinct classes of Fc regions known as antibody isotypes. A B cell receptor is simply a membrane-bound antibody on the surface of the B cell known as IgD. When a B cell becomes a plasma cell it secretes IgM first.  Before plasma cells have a chance to proliferate and greatly improve antigen binding, primary antibody-antigen interactions may be weak.  To make up for this poor recognition, IgM has extra antigen binding sites because it is a pentamer (5 fused antibodies).  As B cells proliferate they can undergo class switching to more specialized isotypes and a stronger secondary response.  IgG is the most common antibody found in plasma and can cross the placenta to provide an unborn baby with some adaptive immunity.  IgA is a dimer (2 fused antibodies) that is designed to cross plasma membranes. It is found in breast milk and the digestive tract. Finally, IgE is an antibody often implicated in allergies due to its tendency to bind Fc receptors on basophils and the similar mast cells.

Figure 22.33: Antibodies, especially IgM antibodies, agglutinate bacteria by binding to epitopes on two or more bacteria simultaneously. When multiple pathogens and antibodies are present, aggregates form when the binding sites of antibodies bind with separate pathogens.

Figure 22.34: Antibodies serve as opsonins and inhibit infection by tagging pathogens for destruction by macrophages, dendritic cells, and neutrophils. These phagocytic cells use Fc receptors to bind to IgG-opsonized pathogens and initiate the first step of attachment before phagocytosis.

Figure 22.35: Neutralization involves the binding of specific antibodies to antigens found on bacteria, viruses, and toxins, preventing them from attaching to target cells.

Antibodies facilitate immune functions by several methods. The flexible antigen-binding arms allow antibodies to induce agglutination (clumping) of pathogens, making them bigger targets, reducing mobility and the ability to adhere to body surfaces. Phagocytes such as neutrophils and macrophages can bind antibodies with Fc receptors enhancing phagocytosis. Thus, like C3b, antibodies facilitate opsonization (enhancing phagocytosis via opsonin coating). Finally, antibodies are relatively large proteins that can block biologically important molecules on the pathogen’s surface in a process of neutralization.

Development and Proliferation

Figure 22.36: Generating Lymphocyte Receptor Variability. (a) As a germ-line B cell matures, an enzyme called DNA recombinase randomly excises V and J segments from the light chain gene. Splicing at the mRNA level results in further gene rearrangement. As a result, (b) each antibody has a unique variable region capable of binding a different antigen.

The human genome only codes for approximately 20,000 protein genes. So, how does our immune system make the billions of different T and B cell receptors needed to bind any potential antigen? During development, different families of genes are ʻāwili (shuffled) and nucleotides randomly inserted to create a huge variety of lymphocyte receptors each with unique antigen-binding sites. This process is dependent on the action of recombination-activating genes (RAGs).  Remember all WBCs are born in the bone marrow.  From there, T cells migrate to the thymus to mature whereas B cells remain in the bone marrow.

Figure 22.37: Differentiation of T Cells within the Thymus: Immature T-cells, called thymocytes, enter the thymus and go through a series of developmental stages that ensures both function and tolerance before they leave and become functional components of the adaptive immune response.

Both T and B cells undergo a similar two-step maturation process. The first step is called positive selection. During this phase, lymphocytes with the cell surface receptors that bind your MHC molecules receive signals to keep maturing. The second step is negative selection. Here, T or B cell receptors that bind your own antigens presented with MHC, called self-antigens, receive a negative signal and are destroyed. This is also known as central tolerance because your immune system is customized to tolerate your self-antigens. Negative selection must be completed to prevent the formation of autoimmune diseases (pathologic adaptive immune responses against your own tissues).

Immunological Memory and Hypersomatic Mutation

Figure 22.38: Clonal Selection of B Cells: During a primary B cell immune response, both antibody-secreting plasma cells and memory B cells are produced. These memory cells lead to the differentiation of more plasma cells and memory B cells during secondary responses.

Activation and proliferation of T cells and B cells typically occurs in the cortical area of lymph nodes. Naïve lymphocytes circulate the body through the cardiovascular system, entering lymph nodes along with lymph or more directly through high endothelial venules (HEV).  During clonal expansion, newly generated T cells have identical receptors as their parent cell.  B cells proliferate as germinal centers within lymph node nodules, undergoing a process called hypersomatic mutation. This allows genes encoding the antigen-binding regions of the B cell receptor (and antibody) to be altered. The selected B cells undergo clonal expansion with varying ability to bind the original antigen. The new clones that bind the antigen more strongly will again proliferate with hypersomatic mutation, and so on. In this way, the binding strength of the B cell receptor and secreted antibodies enhances over time. During an immune response, proliferating Th, Tc or B cells generate some memory lymphocytes. Potentially living decades, these cells can be readily reactivated providing long-term immunity (immunological memory).

Active vs. Passive and Natural vs Artificial Immunity

Figure 22.39: Primary and secondary immune adaptive response: This graph illustrates the primary and secondary immune responses related to antibody production after an initial and secondary exposure to an antigen. Notice that the secondary response is faster and provides a much higher concentration of antibody.

The first time you are exposed to an antigen, long-lived memory lymphocytes are generated providing an army of defense in case you are exposed to the same or similar pathogen again. This is your immune system’s primary adaptive response. Your secondary adaptive response occurs upon reexposure. This time the immune system already has lots of pathogen-specific memory cells to prevent disease. However, there is a lag time between first exposure and a strong immune response. It takes time for Th cells to multiply and activate Tc and B cells. Then, these effector cells also have to multiply and produce memory cells.  Upon a second exposure, even more memory cells and antibodies will be generated. Also, plasma cells will switch from producing IgM to the more effective IgG antibodies. Memory cells can impart immunological resistance to disease over your life span.

Figure 22.40: The four classifications of immunity. (credit top left photo: modification of work by USDA; credit top right photo: modification of work by “Michaelberry”/Wikimedia; credit bottom left photo: modification of work by Centers for Disease Control and Prevention; credit bottom right photo: Airman 1st Class Destinee Doughert / U.S. Air Force; Public Domain)

The generation of memory cells and antibodies due to exposure to an antigen is called active immunity. Active immunity can be natural or artificial. Active natural immunity occurs when normal exposure to a pathogen or toxin causes the immune response. Artificial immunity, such as vaccines, occurs when an antigen is intentionally injected into the body for the sake of generating antibodies and memory lymphocytes. In either case, it usually takes a few weeks for active immunity to reach full strength.  Passive immunity occurs when antibodies are transferred from one individual to another. This occurs naturally during pregnancy and breastfeeding. During pregnancy, IgG antibodies can cross from the maternal to fetal tissues of the placenta. IgA antibodies are found in breastmilk. The transfer of these antibodies imparts the adaptive immunity profile of the mother to the child whose immune system hasn’t yet developed a strong repertoire of mature lymphocytes. There is also passive artificial immunity, which occurs when antibodies are transferred from one person to another. This has traditionally been done using serum from someone previously exposed to a pathogen to prevent disease in another.

22.5 Specific Diseases

As we have learned, foreign antigen bound to MHC is required for an effective adaptive immunity response.  Not all foreign molecules have equal antigenicity (capable of binding T or B cell receptors).  Once more, a foreign molecule with high antigenicity may not have a high degree of immunogenicity (capable of initiating effective immune responses). If a pathogen is able to avoid destruction by your immune system, it may cause disease.  Not all diseases are infectious (able to spread from person to person).  Some diseases are endemic (common within a population).  Usually this means that the population as a whole will have some resistance to the pathogen in the form of antibodies and memory lymphocytes despite it persisting at a relatively constant level. If an infectious disease spreads to a new area where a population has no immunity, it may spread very quickly causing an maʻi ahulau (epidemic).  In some cases, newly emerging pathogens will spread throughout the world population causing a pandemic (pan = all).

Rat Lungworm Disease

The life cycle of angiostrongyliasis	Adult female worm of Angiostrongylus cantonensis recovered from rat lungs with characteristic barber-pole appearance (anterior end of worm is to the top). Scale bar = 1 mm.

Figure 22.41: Angiostrongylus cantonensi 

Rat lungworm disease, or angiostrongyliasis, is a disease that affects the central nervous system. Humans get infected after ingestion or exposure to the larvae of a parasitic nematode (roundworm parasite), Angiostrongylus cantonensis. The larvae are eaten by slugs or snails. In Hawaii, they are commonly found on raw, uncooked leafy green vegetables. The presence of the parasite in the human body results in a rare type of meningitis, that ranges from mild to severe. Research is still ongoing, but the infected meninges is linked to increased eosinophil count, which helps to kill the parasites but may result in an increased acute inflammatory response. Symptoms include severe headache and stiffness of the neck, tingling or painful feelings in the skin or extremities, low-grade fever, nausea, and vomiting starting 1-3 weeks after infection and can last for months or even years. It appears that individuals can get infected with rat lungworm disease more than once, indicating limited immunity to the pathogen that causes it.

Acquired Immune Deficiency Syndrome (AIDS)

A diagram including the early symptoms of HIV ( Human Immunodeficiency Virus) and where it appears in the body.	The HIV replication cycle

Figure 22.42: HIV Symptoms and Replication

The human immunodeficiency virus (HIV) is an infection that may lead to acquired immunodeficiency syndrome (AIDS), a serious and lethal disease characterized by a greatly weakened immune system. The virus is transmitted through semen, vaginal fluids, and blood. In the United States, HIV is mainly transmitted by having sex or sharing syringes and needles with someone who is infected. Like all viruses, HIV needs living host cells to replicate. Upon introduction to the body, it sticks to target cells and tricks the target cells into internalizing it. Once in the host cell, this virus utilizes reverse transcriptase, using its viral RNA to synthesize DNA. This process is opposite to the normal process of genetic transcription and thus viruses that replicate in this manner are called retroviruses.

Figure 22.43: HIV Disease Progression Seroconversion, the rise of anti-HIV antibody levels and the concomitant decline in measurable virus levels, happens during the first several months of HIV disease. Unfortunately, this antibody response is ineffective at controlling the disease, as seen by the progression of the disease towards AIDS, in which all adaptive immune responses are compromised.

Sometimes, but not always, flu-like symptoms occur in the first 1 to 2 weeks after infection. This is later followed by seroconversion. Seroconversion is the reciprocal relationship between virus levels in the blood and antibody levels. As the antibody levels rise, the virus levels decline, and this is a sign that the immune response is at least partially effective. The anti-HIV antibodies formed during seroconversion are the basis for most initial HIV screening done in the United States. Because the seroconversion time varies between individuals, a second test is given months after the first to confirm a negative result.

After seroconversion, the amount of virus circulating in the blood drops and stays low for several years. During this time, the levels of CD4 T helper cells decline steadily until the immune response is so weak that opportunistic diseases begin leading to death. HIV needs the CD4 and other receptors to get inside cells. HIV, therefore, severely hinders CD4 T helper cells which are required for both branches of the adaptive immune system; cell-mediated and humoral immunity.

Treatment for the disease consists of drugs that target virally encoded proteins that are necessary for viral replication but are absent from normal human cells. This approach has been successful in significantly prolonging the lives of HIV-positive individuals. Unfortunately, HIV is good at escaping recognition by the immune system.  It mutates surface antigens at a high rate making it difficult to mount a strong immune response. HIV vaccines have been in development for 30 years and still none have proven adequately effective.

Coronavirus

Figure 22.44: Coronavirus: Colorized scanning electron micrograph of a cell (teal and green) infected with a variant strain of SARS-CoV-2 virus particles (UK B.1.1.7- purple and pink), isolated from a patient sample. Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland.

Coronaviruses are a family of RNA viruses found in various types of animals. They are called coronaviruses due to their resemblance to the lā (sun). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel strain responsible for coronavirus disease-2019 (COVID-19) that was officially declared a worldwide pandemic in the year 2020. The fact that this infectious virus can be transmitted via respiratory droplets and possibly even aerosols by both symptomatic and asymptomatic people has made it difficult to control. COVID-19 affects individuals differently and symptoms range from mild to severe. Symptoms may include a cough, head and body aches, and sometimes loss of taste and/or smell.  Most of those infected recover in about 10 days just as adaptive immune responses are reaching full strength.  In more severe cases, pneumonia, respiratory failure, shock and death may occur. Age correlates strongly with disease severity with the elderly having the worst prognosis.  By January 2023, the CDC reported more than 100 million Americans had acquired COVID-19 with just over one million deaths.

Allergies and hypersensitivities

Figure 22.45: Immunological hypersensitivity: On first exposure to an allergen in a susceptible individual, antigen-presenting cells process and present allergen epitopes with major histocompatibility complex (MHC) II to T helper cells. B cells also process and present the same allergen epitope to TH2 cells, which release cytokines IL-4 and IL-13 to stimulate proliferation and differentiation into IgE-secreting plasma cells. IgE binds to mast cell Fc receptors. Upon subsequent exposure, the allergen cross-links mast cell-bound IgE causing the release of granules (degranulation) resulting in the symptoms of type I hypersensitivity reactions.

Immunological hypersensitivity is an excessive, potentially harmful overreaction to an antigen.  There are four types.  Type I hypersensitivity (immediate hypersensitivity) involves antigens called allergens. Upon first exposure to an allergen a susceptible person will often be asymptomatic but develop anti-allergen IgE antibodies that bind receptors on mast cells and basophils. Subsequent exposure to the same allergen causes mast cells to release histamine and other chemicals, increasing inflammation resulting in the symptoms commonly associated with an allergic reaction.

Symptoms of inhaled allergens from substances such as mold, dust, pollen, and animal dander are nasal edema and runny nose caused by the increased vascular permeability and increased blood flow of nasal blood vessels. Most allergens are in themselves nonpathogenic and therefore mostly harmless. Some individuals develop mild allergies, which are usually treated with antihistamines. However, others develop severe allergies in response to allergens in bee and wasp venoms, toxins in plants, and some foods such as nuts, milk, eggs, and shellfish. Severe allergies may cause anaphylactic shock, which can potentially be fatal within 20 to 30 minutes if untreated. Because epinephrine raises blood pressure and relaxes bronchial smooth muscle, it is routinely used to counteract the effects of anaphylaxis and can be lifesaving. Patients with known severe allergies are encouraged to always keep automatic epinephrine injectors with them, especially when away from easy access to professional emergency healthcare.

Figure 22.46: Skin-Prick Test: Results of an allergy skin-prick test to test for type I hypersensitivity to a group of potential allergens. A positive result is indicated by a raised area (wheal) and surrounding redness (flare). (credit: modification of work by “OakleyOriginals”/Flickr)

Figure 22.47: Type III hypersensitivities and the systems they affect. (a) Immune complexes form and deposit in tissue. Complement activation, stimulation of an inflammatory response, and recruitment and activation of neutrophils result in damage to blood vessels, heart tissue, joints, skin, and/or kidneys. (b) If the kidneys are damaged by a type III hypersensitivity reaction, dialysis may be required. (Credit b:Tech. Sgt. Bennie J. Davis III / US Air Force; Public Domain)

Allergists use skin testing to identify allergens in some types of hypersensitivities. In skin testing, allergen extracts are injected into the epidermis. A positive result typically manifests within 30 minutes as a soft, pale swelling at the site surrounded by a red zone called the wheal and flare response caused by the release of histamine and the granule mediators. The soft center is due to fluid leaking from the blood vessels and the redness is caused by the increased blood flow that results from the dilation of local blood vessels.

Figure 22.48: Type IV Hypersensitivity: Exposure to hapten antigens in poison ivy can cause contact dermatitis, a type IV hypersensitivity. (a) The first exposure to poison ivy does not result in a reaction. However, sensitization stimulates helper T cells, leading to production of memory helper T cells that can become reactivated on future exposures. (b) Upon secondary exposure, the memory helper T cells become reactivated, producing inflammatory cytokines that stimulate macrophages and cytotoxic T cells to induce an inflammatory lesion at the exposed site. This lesion, which will persist until the allergen is removed, can inflict significant tissue damage if it continues long enough.

Type II hypersensitivity involves IgG and IgM antibodies that bind your own cells leading to complement activation and subsequent cellular destruction via the MAC.  Type III hypersensitivity also involves IgG antibodies but here immune complexes are formed that cause localized inflammation often in the joints or kidney.  Finally, type IV hypersensitivity (aka delayed hypersensitivity) is an antibody-independent response with tissue damage being primarily caused by T cells and macrophages.

Figure 22.49: Types of Hypersensitivities: Components of the immune system cause four types of hypersensitivities. Notice that types I–III are B-cell/antibodymediated hypersensitivities, whereas type IV hypersensitivity is exclusively a T-cell phenomenon.

Autoimmune

Figure 22.50: Goiter, a hypertrophy of the thyroid, is a symptom of Graves disease and Hashimoto thyroiditis.

Figure 22.51: Exophthalmia, or Graves ophthalmopathy, is a sign of Graves disease. (credit: modification of work by Jonathan Trobe, University of Michigan Kellogg Eye Center)

Figure 22.52: Rheumatoid arthritis: The radiograph (left) and photograph (right) show damage to the hands typical of rheumatoid arthritis. (credit right: modification of work by “handarmdoc”/Flickr)

Figure 22.53: Lupus: SLE. (a) Systemic lupus erythematosus is characterized by autoimmunity to the individual’s own DNA and/or proteins. (b) This patient is presenting with a butterfly rash, one of the characteristic signs of lupus.

Sometimes, the adaptive immune system will erroneously attack your body’s healthy cells. When this happens, the person is said to have an autoimmune disease. The trigger for these diseases is often unknown with both environmental and genetic factors suspected in most cases. Treatments are usually based on resolving the symptoms using immunosuppressive and anti-inflammatory drugs such as steroids. The symptoms vary depending on the specific type of autoimmune disease. For instance, rheumatoid arthritis (RA) is an autoimmune disease that causes pain, stiffness, and loss of function of the joints. It is associated with high levels of IL-1, IL-6, TNF-𝜶 which may cause inflammation of the synovial membranes among other tissues. Systemic lupus erythematosus (SLE), an autoimmune disease often involves anti-nuclear protein antibodies resulting in systemic inflammation. Symptoms include joint aches, fever, fatigue in addition to the characteristic skin rashes and swelling. Grave’s disease is the most common cause of hyperthyroidism.  It is caused by thyroid stimulating antibodies mimicking TSH. Irritability, sleeping problems, tachycardia, heat sensitivity, weight loss, eye bulging and other eye problems are common. Treatments may include removal of the thyroid followed by life-long hormone treatment.

Environmental triggers seem to play a large role in autoimmune responses. One explanation for the breakdown of central tolerance is that, after certain bacterial infections, an immune response to a component of the bacterium cross-reacts with a self-antigen. This mechanism is seen in rheumatic fever as a result of infection with Streptococcus, the etiologic agent of strep throat. The antibodies generated to this pathogen’s M protein cross-react with an antigenic component of heart myosin, a major contractile protein of the heart that is critical to its normal function. The antibody binds to these molecules and activates complement proteins, causing inflammation of the heart, especially to the heart valves.

Despite the link between bacteria and rheumatic fever, some theories propose that exposure to a diversity of common pathogens may reduce the prevalence of hypersensitivities and autoimmune responses. The fact that allergies and autoimmune diseases are rare in countries that have a high incidence of infectious diseases supports this idea.  The overuse of antimicrobials in soaps, toys and other products can compromise the healthy microbiota, promote antibiotic resistance, in addition to preventing your immune system from being properly primed to the antigens in the surrounding environment.

Table 22.7: Autoimmune Diseases – OpenStax Microbiology

Stress and the Immune System

The human response to stress includes both physical and psychological symptoms. Acute (short term) stress can be beneficial such as that brought on by exercise.  Chronic stress (an ongoing state of physiological arousal), however, has been linked to increased illness. Chronic stress activates the sympathetic (“fight or flight”) division of the autonomic nervous system. Through a cascade of physiological events, sympathetic stimulation results in the release of cortisol (the “stress” hormone). Persistent high levels of cortisol reduces levels of immature B cells. Decreased levels of B cells result in reduced antibody production in the body, impairing the adaptive immune response. Additionally, norepinephrine release associated with activation of the sympathetic nervous system further facilitates inflammation by promoting the release of inflammatory mediators. This combination of dampened adaptive immune function and constant inflammation makes the body less efficient at controlling pathogens while also causing damage to self tissues.  Being more susceptible to disease and the discomfort of inflammation exacerbates the stress level, thus further suppressing adaptive immunity and increasing inflammation in a negative spiral.

It has been reported that chronic inflammation is linked to more than 50% of all deaths worldwide. Poor diet, obesity, physical inactivity, chronic stress, environmental pollutants, and poor sleep are common causes of systemic chronic inflammation that can lead to cardiovascular disease, cancer, diabetes mellitus, kidney disease, and autoimmune and neurodegenerative disorders. Prevention of chronic inflammation includes conscious lifestyle changes (increasing exercise and eating a plant-based whole foods diet) and a focus on positive changes to both the social and physical environment.

Psychoneuroimmunology is the field of study that focuses on the link between the immune, nervous and endocrine systems.  Physical disorders or diseases whose symptoms are brought about or worsened by stress and emotional factors are called psychophysiological disorders. A list of frequently encountered psychophysiological disorders is provided in the following table:

Table 22.8: Types of Psychophysiological Disorders (adapted from Everly & Lating, 2002) – OpenStax Psychology 2e

The mechanism whereby stress causes inflammation is thought to involve the stress hormone cortisol promoting cytokine production.  This results in chronic innate immune system responses. Another potential link involves C-Reactive Protein (CRP). CRP, a protein synthesized by the liver, is secreted into the bloodstream in response to inflammation. Elevated CRP is found in individuals with cardiovascular disease (CVD) and recent studies also revealed a correlation between CRP and work-related stress. Reducing stress as a possible means of reducing chronic inflammation and associated psychophysiological disorders may be an important step in improving immune system function.

Chapter Summary

Quiz

Citations:

ʻŌlelo Noʻeau — Pukui #1252

https://doi.org/10.1006/jhge.2001.0325 and cdc.gov/leprosy

https://doi.org/10.3389/fimmu.2021.646333

Liu YZ, Wang YX, Jiang CL. Inflammation: The Common Pathway of Stress-Related Diseases. Front Hum Neurosci. 2017;11:316. Published 2017 Jun 20. doi:10.3389/fnhum.2017.00316

https://www.cdc.gov/hiv/risk/index.html

McGregor BA, Murphy KM, Albano DL, Ceballos RM. Stress, cortisol, and B lymphocytes: a novel approach to understanding academic stress and immune function. Stress. 2016;19(2):185-191. doi:10.3109/10253890.2015.1127913

Citations:

Bancos, S., Bernard, M. P., Topham, D. J., & Phipps, R. P. (2009). Ibuprofen and other widely used non-steroidal anti-inflammatory drugs inhibit antibody production in human cells. Cellular immunology, 258(1), 18–28. https://doi.org/10.1016/j.cellimm.2009.03.007

Minta, J. O., Urowitz, M. B., Smythe, H. A., & Isenman, D. E. (1983). Effect on the human complement system of the major non-steroidal anti-inflammatory drugs: aspirin, indomethacin, phenylbutazone, oxyphenbutazone, and sulindac. Clinical and experimental immunology, 53(3), 555–561.

Citation: Prasad A. S. (2008). Zinc in human health: effect of zinc on immune cells. Molecular medicine (Cambridge, Mass.), 14(5-6), 353–357. https://doi.org/10.2119/2008-00033.Prasad

Citation: https://www.nutritionvalue.org/Poi_nutritional_value.html#:~:text=Poi%20contains%20269%20calories%20per,mg%20of%20cholesterol%20per%20serving.

Citation: Furman, D., Campisi, J., Verdin, E. et al. Chronic inflammation in the etiology of disease across the lifespan. Nat Med 25, 1822–1832 (2019). https://doi.org/10.1038/s41591-019-0675-0

Key Terms

acquired immunodeficiency syndrome (AIDS) 

a serious and lethal disease caused by human immunodeficiency virus (HIV) and characterized by a greatly weakened immune system

active immunity 

immunity developed from an individual’s own immune system

adaptive immunity

relatively slow but very specific and effective immune response involving lymphocytes

afferent lymphatic vessels 

lead into a lymph node

agglutination

clumping, the amassing of cells due to antibody binding

agranulocytes 

WBCs that aren’t granulocytes including monocytes, dendritic cells and lymphocytes

allergens

antigens responsible for type I hypersensitivity

anchoring filaments

projecting, hair-like structures that prevent lymphatic capillary collapse

angiostrongyliasis

rat lungworm disease, caused by the parasitic nematode Angiostrongylus cantonensis carried by slugs and snails

antibody 

antigen-specific protein secreted by plasma cells; immunoglobulin

antigen 

molecule recognized by the receptors of B and T lymphocytes

antigenicity

the degree to which an antigen binds a T or B cell receptor

antigen presentation 

binding of processed antigen to the protein-binding cleft of a major histocompatibility complex molecule

antihistamine

a drug that counteracts the effects of histamine

antimicrobial peptides

a relatively short chain of amino acids with anti-bacterial, -viral or -fungal properties

antipyretic

fever-reducing medications

APC

an antigen presenting cells, namely macrophages and dendritic cells

artificial immunity

occurs when an antigen is intentionally injected into the body for the sake of generating antibodies and memory lymphocytes such as with vaccines

autoimmune diseases 

a pathologic adaptive immune response against your own tissues

bacteria

single-celled, prokaryotic microorganisms 

basophil

granulocytes with histidine containing granules and are implicated in allergies

bronchus-associated lymphoid tissue (BALT)

bronchus-associated lymphoid tissue, lymphoid nodule associated with the respiratory tract

B cell 

lymphocyte that acts by differentiating into an antibody-secreting plasma cell

C3

complement protein that fragments into C3a and C3b. C3a enhances inflammation and C3b is an opsonin and activates C5 

C5

complement protein that fragments into C5a and C5b. C5a enhances inflammation C5b initiates formation of the MAC by triggering the interaction of C6, C7, C8 and several C9s

CAMs

cell adhesion molecules that promote intercellular binding

CD4⁺ T cells

 T_h , helper T cells, T cells that express the surface protein CD4

central tolerance 

B cell tolerance induced in immature B cells of the bone marrow

cell-mediated immunity

adaptive immunity activated by helper T cell subclass T_h1, involving T_C

chemokine 

soluble, long-range, cell-to-cell communication molecule

chemotaxis

cells following a chemical concentration gradient such as leukocytes following a chemokine trail toward a site of injury 

chyle 

lipid-rich lymph inside the lymphatic capillaries of the small intestine

cisterna chyli 

bag-like vessel that forms the beginning of the thoracic duct

classical pathway 

complement proteins are activated by the presence of pathogen bound antibodies

class switching

ability of B cells to change the class of antibody they produce without altering the

specificity for antigen, aka isotype switching 

clonal expansion 

proliferation of B lymphocytes with a specific antigen receptor into a population with varying degree of antigen binding strength

complement 

enzymatic cascade of constitutive blood proteins that have anti-pathogen effects, including

the direct killing of bacteria

constant region 

domain part of a lymphocyte antigen receptor that does not vary much between different

receptor types

COVID-19 

coronavirus disease-2019 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for a worldwide pandemic in the year 2020

C-Reactive Protein (CRP)

a protein associated with stress, inflammation and psychophysiological disorders

CSFs

colony-stimulating factors, induce proliferation of WBCs in the bone marrow

cytokine 

soluble, short-range, cell-to-cell communication molecule

cytotoxic T cells (Tc) 

T lymphocytes with the ability to induce apoptosis in target cells 

DAMPs 

damage-associated molecular patterns recognized by PRRs of innate immunity

defensin

a chemical class type of AMPs

delayed hypersensitivity (type IV) 

T cell-mediated immune response against pathogens infiltrating interstitial tissues, causing cellular infiltrate

dendritic cell

an APC similar to macrophages

dermcidin

a chemical class type of AMPs

diapedesis

leukocytes squeezing between endothelial, out of the blood into the surrounding tissues

disease

abnormal functioning part of the body, illness, sickness or ailment

effector B cells

plasma cells, activated B lymphocytes

effector T cells 

immune cells with a direct, adverse effect on a pathogen

efferent lymphatic vessels 

lead out of a lymph node

endemic

a disease common within a population

eosinophil

granulocytes specialised for attaching parasites such as worms

epidemic

the rapid spreading or temporary prevalence of disease in a population

epitope

the specific region of an antigen that binds to a T or B cell receptor

Fab

fragment of antigen binding, that part of the antibody that binds antigen

fas ligand (FasL)

molecule expressed on cytotoxic T cells and NK cells that binds to the fas molecule on a

target cell and induces it do undergo apoptosis

Fc receptor

a membrane bound protein on phagocytes that binds the Fc region of an antibody

Fc region 

in an antibody molecule, the site where the two termini of the heavy chains come together;

many cells have receptors for this portion of the antibody, adding functionality to these molecules

fever

abnormally high body temperature, aka pyrexia

fungi

eukaryotic organisms distinguished from animals and plants by chitin-containing cell walls among other features 

germinal center 

clusters of rapidly proliferating B cells found in secondary lymphoid tissues

granzyme 

apoptosis-inducing substance contained in granules of NK cells and cytotoxic T cells

granulocytes

WBCs that have granules; neutrophils, eosinophils and basophils

Grave’s disease 

an autoimmune disease causing hyperthyroidism resulting in tachycardia, heat sensitivity, weight loss, eye bulging among other symptoms

Hansen’s disease (leprosy)

a disease caused by a Mycobacterium leprae infection primarily affecting the peripheral nervous system, skin, and nasal mucosa

helper T cells (T_h) 

T cells that secrete cytokines to enhance other immune responses, involved in

activation of both B and T_c cell lymphocytes

high endothelial venules (HEV)

vessels containing unique endothelial cells specialized to allow migration of

lymphocytes from the blood to the lymph node

histamine 

vasoactive mediator in granules of basophils and mast cells and is the primary cause of allergies and anaphylactic shock

human immunodeficiency virus (HIV) 

is a virus capable of causing acquired immunodeficiency syndrome (AIDS), a serious and lethal disease characterized by a greatly weakened immune system

humoral immunity

adaptive immunity involving T_h2 stimulating B cells to secrete antibodies

hypersomatic mutation

the process of the antigen-binding regions of the B cell receptor (and antibody) to be altered during B cell clonal expansion 

hyperemia 

increased blood flow near the site of inflammation

hypersensitivity

an excessive, potentially harmful overreaction to an antigen

IgA 

antibody whose dimer is secreted by exocrine glands, is especially effective against digestive and respiratory pathogens, and can pass immunity to an infant through breastfeeding

IgD 

class of antibody whose only known function is as a receptor on naive B cells; important in B cell activation

IgE 

antibody that binds to mast cells and causes antigen-specific degranulation during an allergic response

IgG 

main blood antibody of late primary and early secondary responses; passed from carrier to unborn child via placenta

IgM 

antibody whose monomer is a surface receptor of naive B cells; the pentamer is the first antibody made blood plasma during primary responses

IL-4

interleukin-4, promotes T_h² and plasma cell development among other functions

immediate hypersensitivity (type I) 

IgE-mediated mast cell degranulation caused by crosslinking of surface IgE by antigen

immune system series of barriers, cells, and soluble mediators that combine to response to infections of the body with pathogenic organisms

immunogenicity

the degree by which an antigen induces an immune response

immunoglobulin 

protein antibody; occurs as one of five main classes

immunological memory 

ability of the adaptive immune response to mount a stronger and faster immune response upon re-exposure to a pathogen

infectious

a disease capable of transmitting from person to person

inflammation 

basic innate immune response characterized by heat, redness, pain, and swelling

innate immunity 

rapid but relatively nonspecific immune responses

interferons (INFs)

early induced proteins made in virally infected cells that cause nearby cells to make antiviral proteins

interleukins

chemical messengers released by WBCs to stimulate others in an autocrine or paracrine manner

interstitial fluid (IF)

fluid between cells and tissues, excluding plasma or lymph

kinins

peptides that contribute to pain, inflammation and smooth muscle contraction

lacteal

lymphatic capillaries of the gut that absorb bile to form chyle

lectin pathway

complement activated by the presence of certain carbohydrates typical of some bacteria

leukocyte (aka WBC)

white blood cells, cells of the immune system

leukocytosis

a high WBC count

leukopoiesis

leukocyte proliferation in bone marrow

lymph 

fluid contained within the lymphatic system

lymph node 

one of the bean-shaped organs found associated with the lymphatic vessels

lymphatic capillaries 

smallest of the lymphatic vessels and the origin of lymph flow

lymphatic system 

network of lymphatic vessels, lymph nodes, and ducts that carries lymph from the tissues and back to the bloodstream.

lymphatic trunks 

large lymphatics that collect lymph from smaller lymphatic vessels and empties into the

blood via lymphatic ducts

lymphatic vessels 

Lymphatic vasculature that form  from fused smaller lymphatic capillaries, these deliver lymph to and from lymph nodes

lymphocytes 

white blood cells characterized by a large nucleus and small rim of cytoplasm

MAC

membrane attack complex, the interaction of C5, C6, C7, C8 and several C9s creates a hole in bacterial membranes disrupting the targeted cell

macrophage 

ameboid phagocyte found in several tissues throughout the body

major histocompatibility complex (MHC) 

gene cluster whose proteins present antigens to T cells 

MALT

mucosa-associated lymphoid tissue, lymphoid tissue associated with the digestive tract and respiratory system

margination

instead of the middle of the blood vessel, cells travel along the wall by sticking and rolling via CAM interactions 

mast cell 

cell found in the skin and the lining of body cells that contains cytoplasmic granules with

vasoactive mediators such as histamine (similar to basophils)

memory lymphocytes 

long-lived T or B cell reserved for future exposure to a pathogen

MHC class I

found on most cells of the body, it binds to the CD8 molecule on T cells

MHC polygeny 

multiple MHC genes and their proteins found in body cells

MHC polymorphism 

multiple alleles for each individual MHC locus

microbiota (aka normal flora)

the typical bacteria, viruses and other microbes associated with healthy populations

mini flaps

openings that allow IF to enter lymphatic capillaries, becoming lymph 

monocyte 

precursor to macrophages and dendritic cells seen in the blood

naïve lymphocyte 

mature B or T cell that has not yet encountered antigen for the first time

natural killer cell (NK) 

cytotoxic lymphocyte of innate immune response

natural immunity 

the normal exposure to a pathogen or toxin causing an immune response

negative selection 

selection against thymocytes in the thymus that react with self-antigen neutralization inactivation of a virus by the binding of specific antibody

neutralization

antibodies blocking disease promoting molecules on a pathogens such as adherence proteins 

neutrophil 

phagocytic white blood cell recruited from the bloodstream to the site of infection via the

bloodstream

NETs

neutrophil extracellular traps, released DNA that traps and thereby sequestering pathogens

NSAIDs

non-steroidal anti-inflammatory drugs such as aspirin and ibuprofen

opportunistic diseases 

pathogens that don’t normally cause disease in healthy individuals but can when the immune system is compromised in some way

opsonization 

enhancement of phagocytosis by the binding of antibody or antimicrobial protein

PAMPS

pathogen associated molecular patterns that are recognized by PRRs of the innate immune system

pandemic

an epidemic of a large area such as an entire country, continent, or planet

paresthesia

an abnormal sensation, such as prickling, itching, etc.

passive immunity 

transfer of immunity to a pathogen to an individual that lacks immunity to this pathogen

usually by the injection of antibodies

pathogen

a pathology-inducing agent such as certain bacteria, fungi or viruses

pathogenicity

the extent or ability of a pathogen to cause disease

pattern recognition receptor (PRR) 

leukocyte receptor that binds to specific cell wall components of different bacterial species

perforin molecule in NK cell and cytotoxic T cell granules that form pores in the membrane of a target cell

perforin

an enzyme that forms holes in the plasma membrane, released by NK and T_c cells

Peyer’s patches

lymphoid follicles associated with distal regions of the small intestine, part of the MALT

phagocyte

a cell capable of phagocytosis, namely neutrophils, macrophages and dendritic cells

phagocytosis 

movement of material from the outside to the inside of the cells via vesicles made from

invaginations of the plasma membrane

plasma cell 

differentiated B cell that is actively secreting antibody

PMN

polymorphonuclear cells, aka granulocytes

positive selection 

selection of thymocytes within the thymus that interact with self, but not non-self, MHC molecules

primary adaptive response 

immune system’s response to the first exposure to a pathogen

primary lymphoid organ 

site where lymphocytes mature and proliferate; red bone marrow and

thymus gland

prion

a protein folded into an abnormal shape that causes normal proteins to also misfold 

prognosis

forecasting the probable outcome of disease including chances of recovery

prostaglandins

lipids associated with inflammation, bronchodilation and many other effects

PRRs (pattern recognition receptors)

receptors on cells of the innate immune system that bind PAMPs and DAMPs

psychoneuroimmunology 

study of the connections between the immune, nervous, and endocrine

systems

psychophysiological disorders

diseases whose symptoms are brought about or worsened by stress and emotional factors 

pyrexia

abnormally high body temperature, aka fever

pyrogens

chemicals that signal the hypothalamus to increase body temperature

recombination-activating genes (RAGs)

the genes responsible for recombining segments and randomly inserting nucleotides into the variable regions of T and B cell receptor genes

red pulp

areas within the spleen where old, damaged RBCs are broken down

regulatory T cells (Treg, suppressor T cells)

class of CD4 T cells that regulates other T cell responses

respiratory pump

the mechanism by which plasma and lymph is drawn toward the heart due to the low pressure in the thoracic cage created by the respiratory system

rheumatoid arthritis (RA) is an autoimmune disease that causes inflammation, pain, stiffness, and loss of function of the joints

rheumatic fever

an infection with Streptococcus resulting in inflammation heart, skin, joints or brain tissue 

right lymphatic duct 

drains lymph fluid from the upper right side of body into the right subclavian

vein

secondary adaptive response 

immune response observed upon re-exposure to a pathogen, which is

stronger and faster than a primary response

secondary lymphoid organ 

sites where lymphocytes mount adaptive immune responses; examples include lymph nodes and spleen

self-antigen

molecules produced by and that do not induce adaptive immune responses of an individual in the absence of autoimmune disease

 seroconversion 

clearance of pathogen in the serum and the simultaneous rise of serum antibody

systemic lupus erythematosus (SLE) 

an autoimmune disease causing inflammation, joint aches, fever, and characteristic skin rashes and swelling 

T cell

a cell type of the adaptive immune system, the two main subtypes being T_H and T_c

T cell-dependent antigen 

antigen that binds to B cells, which requires signals from T cells to make antibody

T cell-independent antigen 

binds to B cells, which do not require signals from T cells to make antibody

T_h1 

cells that secrete cytokines that enhance the activity of T_c

T_h2 

cells that secrete cytokines that induce B cells to differentiate into plasma cells

thoracic duct 

large duct that drains lymph from the lower limbs, left thorax, left upper limb, and the left

side of the head

thymus 

primary lymphoid organ; where T lymphocytes proliferate and mature

tonsils 

lymphoid nodules associated with the nasopharynx

type I hypersensitivity 

immediate response mediated by mast cell degranulation caused by the crosslinking of the antigen-specific IgE molecules on the mast cell surface

type II hypersensitivity 

cell damage caused by the binding of antibody and the activation of complement, usually against red blood cells

type III hypersensitivity 

damage to tissues caused by the deposition of antibody-antigen (immune) complexes followed by the activation of complement

type IV hypersensitivity (aka delayed hypersensitivity) 

an antibody-independent response primarily involving by T cells and macrophages

valves

inward projections within lymphatic capillaries that prevent lymph backflow

variable region 

domain part of a lymphocyte antigen receptor that varies considerably between different

receptor types

vasodilation

an increase in blood vessel diameter

virus

a non-living infectious agent that requires a living cell to multiply

white pulp

areas in the spleen where numerous WBCs are performing immunological functions