Chapter 2 Immunity

4 types of hypersensitivity

Type 1 - IgE mediated Type 2 - Tissue specific Type 3 - Immune complex mediated Type 4 - Cell mediated

Type 4 hypersensitivity

Type IV hypersensitivity involves a delayed processing of the antigen by macrophages. Once processed, the antigen is presented to the T cells (usually helper or cytotoxic cells), resulting in the release of cytokines that cause inflammation and antigen destruction. As opposed to the other types of hypersensitivity, type IV is not antibody mediated These reactions can cause severe tissue injury and fibrosis. Examples of type IV reactions include tuberculin skin testing, transplant reactions, and contact dermatitis from poison ivy. Treatment for type IV reactions is disease specific.

Anaphylaxis

Widespread, immediate systemic reactions resulting from sudden release of mast cell and basophil mediator release is termed anaphylaxis. Anaphylaxis is usually the result of an IgE event, but IgG and immune complex/complement reactions may also occur. These three types of reactions are termed immunologic anaphylaxis. Mast cells and basophils may be activated without IgE, IgG, or immune complexes and the reaction is termed nonimmunologic anaphylaxis (formerly anaphylactoid). Examples of nonimmunologic reactions are red man syndrome, caused by vancomycin administration or erythema; pruritus; and edema with exposure to cold (cold urticaria). Clinically, the underlying immune event in anaphylaxis is often difficult to determine. While most environmental allergies are type I IgE mediated, some are type II and type III, such as when gluten from wheat causes gastrointestinal symptoms (e.g., celiac disease) with a penicillin allergy. Poison ivy, although an environmental allergen, causes a type IV hypersensitivity (see Table 2-5). Treatment of type I reactions may include epinephrine, antihistamines, corticosteroids, and desensitizing injections, all of which will suppress inflammatory activity.

altered immune response

a malfunction at any point in complex immune responses can create a pathologic state exaggeration (hypersensitivity) failure of self recognition (autoimmunity) or diminution (immunodeficiency)

what do Th 2 cells do?

activate B cells to produce antibodies

antigen

any substance that the body recognizes as foreign and can include microogranisms, environmental substances, drugs, and transplanted tissues

alloimmunity: transplants/blood transfusions

ensuring best possible tissue match is critical for transplant success

role of complement system proteins

Five complement system proteins join together to form a large molecule, or membrane attack complex. The membrane attack complex becomes embedded in the plasma membrane of bacteria, creating an opening into which water flows. The influx of water causes the bacterial cells to swell, burst, and die. Other complement proteins stimulate vasodilation in an infected area as a part of the inflammatory response. Some complement proteins increase the permeability of vessels, allowing white blood cells and plasma to pass quickly through them to the infected area. Other complement proteins serve as chemical attractants, drawing macrophages, monocytes, and neutrophils to the infected area where they phagocytize foreign cells. Still other complement proteins bind to microbes, forming a rough coat on the invader that promotes phagocytosis.

Type 3 hypersensitivity

In type III hypersensitivity, circulating antigen-antibody complexes that have not been adequately cleared by the innate blood-borne immune cells accumulate and become deposited in tissues. Characteristics of the antigen-antibody complex will determine where and with what tissue the complex will bind. As opposed to type II reactions, type III reactions are not targeted toward a specific organ. However, tissues often affected in this way include the kidneys, joints, skin, and blood vessels. The accumulation of the complexes triggers the complement system, causing local inflammation and increased vascular permeability; in turn, more complexes accumulate as neutrophils and macrophages are activated. Examples of type III reactions include autoimmune disorders (e.g., systemic lupus erythematosus and glomerulonephritis). The quality of the immune complex changes over time, and there can be several types at one time (e.g., small, intermediate, or large). The changing immune complexes and different types lead to varying symptomatology and causes the remissions and exacerbations seen in type III hypersensitivity. Treatment for type III reactions is disease specific.

host versus graft, graft versus host

Most rejection reactions are classified as host-versus-graft rejection; in other words, the host is fighting the graft. The graft fights the host in another type of reaction, known as graft-versus-host rejection. This potentially life-threatening type of reaction occurs with bone marrow or stem cell transplants. The immunocompetent graft cells recognize the host cells as foreign due to the host having antigens that are not on the graft and organize a cell-mediated (primarily T-cell) attack. The host is usually immunocompromised and unable to fight the graft cells' actions.

cellular mediators

Prostaglandin and another mediator, leukotriene, causes vasodilation and increased vascular permeability Platelet-activating factor acts similarly to leukotrienes and also activates platelets. While the preformed mediators are released immediately, the newly synthesized mediators start 15 minutes to hours after activation Several other mediators that continue to contribute to the inflammatory process are released and/or synthesized.

what is acquired immunity?

Subsequent exposures to the antigen then trigger a quick response because memory cells recall the antigen as foreign and antibody production occurs rapidly. This reaction is referred to as acquired immunity

helper T cells can be subdivided into ?

T-helper (Th) 1 and Th 2

hypersensitivity

inflated or inappropriate response to an antigen result: inflammation and destruction of healthy tissue reactions may be immediate (minutes to hours) or delayed (several hours)

what do Th 1 cells do?

involved in the inflammatory process and activation of macrophages

complement system

involves approx 20 blood plasma proteins and enhances the action of antibodies complement proteins circulate in the blood in an inactive state when foreign substances invade the body, these proteins become activated and several pathways are taken to enhance pathogen destruction and participate in inflammatory response

Type 2 hypersensitivity

involves the destruction of antigens on target cells or tissue antigens may be intrinsic (self) or extrinsic (absorbed through exposure) IgG or IgM antibodies bind with an individual's own specific cell or tissue antigens, activating the complement system. The end result is destruction or a malfunctioning cell. Recognition of these cells by macrophages triggers antibody production. Type II hypersensitivity mechanisms include complement activation, leading to cell lysis, phagocytosis, and neutrophil or cytotoxic (natural killer) cells destroying the targets. Another type II mechanism involves an antibody binding with a cell surface receptor and blocking the action of this receptor Examples of type II reactions include blood transfusion reactions and erythroblastosis fetalis. Treatment for these two reactions focuses on prevention and includes ensuring blood compatibility prior to transfusions, administering medication to suppress immune activity (e.g., corticosteroids and cyclosporine), and preventing maternal antibody development (e.g., Rho[D] with immune globulin [RhoGAM]).

kinin system

kinin system activation leads to development of bradykinin bradykinin causes pain, increased vascular permeability through vasodilation, neutrophil recruitment, and smooth muscle contraction

what are rejection reactions classified by?

timing

when are physical and chemical barriers not completely impenetrable and what happens next?

tiny breaks in skin or lining of respiratory, GI, GU tracts can permit antigen invasion when these barriers are penetrated, the inflammatory response is activated

where do pyrogens go?

travel to hypothalamus, where body temp is controlled they turn up the thermostat in a regulated manner and body is heated up to reach this new temp, resulting in fever fever creates unpleasant environment for bacterial growth mild fevers: spleen and liver remove iron from blood which is required for many bacteria to reproduce fever increases metabolism, which facilitates healing and accelerates phagocytosis

role of suppressor T cells

turn antibody production off

inflammatory response

when cells and body tissues are injured, regardless of the cause (e.g., microorganisms, chemical irritants, immune/genetic defects, hypoxia), a series of reactions referred to as the inflammatory response is triggered part of innate immunity- NONDISCRIMINATORY (same sequence of response occurs no matter the type of injury or prior exposure as there is no memory involved)

helper cells secrete protein CD4+

which is a major target of human immunodeficiency virus (HIV)

mast cells

white blood cells (granulocytes) that are abundantly found in areas exposed to the environment such as the skin, gastrointestinal tract, and respiratory tract and are central to the inflammatory process. release several preformed mediators such as histamine, which stimulates vasodilation causing erythema, edema, and heat also cause synthesis of other mediators such as prostaglandins, which stimulate pain receptors in the area

vaccination response is influenced by

1. antigen characteristic and dose 2. administration route 3. adjuvants added to enhance and modulate response (ex: aluminum based material, oil-in-water emulsions)

optimal immunity requires

1. intact nonspecific defenses (skin, mucous membranes, phagocytes, complement systems) 2. functional lymphatic system 3. innate immune response 4. operational inflammatory response 5. appropriate and adaptive acquired immunity

vaccines fall into 2 categories

1. live, attenuated 2. inactivated

two types of T cells work to destroy antigens

1. regulator cells- helper T cells and suppressor T cells 2. effector cells- killer T cells

chronic tissue rejection

4 months to years after the transplant This reaction is most likely due to an antibody-mediated immune response. Antibodies and complement molecules become deposited in the transplanted tissue vessel walls, resulting in decreased blood flow and ischemia.

APC (antigen presenting cells)

Antigens must be processed and presented to the cell receptor for proper recognition by the T cells. This recognition system is important for the body to distinguish self from nonself. For some antigens, presentation can be accomplished by any cell, but for other antigens to be recognized by T cells, specialized antigen-presenting cells (APCs) are required. The dendritic cells from the bone marrow are important APCs. They are located all over the skin, respiratory system, and gastrointestinal system. Macrophages and B lymphocytes are two other key APCs. The antigen that is in the APC further binds to the major histocompatibility complex (MHC). The MHC encompasses a group of genes involved in immune function. The MHC genes include various cell markers, proteins, and antigens bound to a protein that then presents the antigen to the T cells. In humans, the MHC is called the human leukocyte antigen (HLA) system as the genes are expressed on the surface of the white blood cell. The human MHC and human HLA are synonymous. MHC genes are located on chromosome 6, and two different antigens will be on the cell surfaces—class I and II (i.e., regions). Class I cells include HLA-A, HLA-B, and HLA-C and are located on cells throughout. Class II cells are HLA-D, which are mainly in the immune system (B lymphocytes and monocytes), and are expressed on dendritic cells, macrophages, and B cells (all APCs). Class II cells present to the CD4+ helper T cells while class I cells present to the CD8+ suppressor and cytotoxic T cells. The adaptive system is often dependent on APCs. The MHC/HLA system is critical to understanding organ transplantation and the predisposition to diseases (e.g., rheumatoid arthritis, type 1 diabetes mellitus). Antigen recognition and antigen binding triggers a response by other immune cells. Class III region consist of components of the complement system and class IV has other immune genes such as tumor necrosis factors.

humoral immunity

B cells mature in bone marrow where they differentiate into either memory cells or plasma cells, which produce immunoglobulins these cells eliminate extracellular bacteria, neutralize bacterial toxins, prevent viral reinfection, and produce an immediate inflammatory response

clotting system

activated during infection and injury attracts neutrophils to site of injury and causes increased vascular permeability transformation of fibrinogen into fibrin which is used to wall off the injured area so that foreign substances are contained a meshwork of new cells form to provide support for the healing process blood clotting begins if blood vessels have been damaged

vascular response

acute inflammatory response consists mainly of vascular response that creates cardinal signs 1. erythema 2. edema 3. heat 4. pain at the site of injury These clinical manifestations are the result of the release of preformed mediators and the synthesis of new biochemical mediators from mast cell degranulation

Type 1 Hypesensitivity

allergens activate T cells (usually helper T cells) which bind to mast cells these T cells stimulate B cells to produce IgE antibodies specific to antigen (commonly environmental aka ALLERGY) difference between normal immune response and type 1 hypersensitivity: IgE is produced instead of IgA, IgG or IgM IgE coats mast cells and basophils, making them sensitive to allergen at the next exposure of the same antigen, antigen binds with surface IgE which causes mast call degranulation and mediator release (histamine, cytokines, and prostaglandins) degranulation and mediator release further activates inflammatory process, attracting neutrophils and eosinophils and triggering complement system histamine is the mediator that causes many symptoms immediate inflammation and pruritus reaction can be localized like in asthma, allergic rhinitis and food allergies

4 types of tissue transplants

allogenic: tissue is used from same species and is of similar tissue type, but not identical (most transplants) syngeneic: use tissue from identical twin of the host autologous: host and donor are same person, ex: saving blood for next surgery xenogenic: tissue from other species, ex: pig heart valves

autoimmunity

body's normal defenses become self-destructive fail to identify self antigens within the host from nonself foreign antigens under normal circumstances, the immune system has capability to tolerate self-antigens and regulate them to avoid maladaptive immune response -- these mechanisms are central and peripheral tolerance

adaptive immunity

body's own individual immune system recognize and attack antigens that make it through innate defenses often stimulated and primed during innate defense

T cells vs B cells

both cells mingle with antigens as they circulate throughout body's fluids and peripheral lymphoid tissue such as tonsils, lymph nodes, spleen and intestinal lymphoid tissue this interaction serves either to destroy antigen (T cell function/cellular immunity) or produce antibodies against antigen (B cell function/humoral immunity) T cells and B cells have receptors on their surfaces that develop during maturation process and are prepared to recognize antigens

adaptive (acquired) immunity

can take 7-10 days to provide protection, but is specific to the antigen

What causes autoimmune diseases?

cause is unclear exogenous trigger and endogenous abnormalities (viral, genetic, medicinal, hormonal, environmental) with multiple mechanisms likely contribute to autoimmune development exogenous trigger may cause autoimmunity when antigen (pathogen) looks like an antigen already present (molecular mimicry) - immune system attacks foreign antigen and self-antigen because they look so similar Some antigens such as viruses or bacteria act as superantigens and have the ability to bind to T cells that are nonspecific and mount an immune response. Some antigens modify the immune response (e.g., adjuvant effect) by increasing the immunogenicity (provoking immune response). Several endogenous abnormalities can contribute to autoimmunity and can include abnormal antigen presentation. The immune system may have problems clearing cellular debris such as apoptotic cells. Other endogenous abnormalities include B cells and T cells responding inappropriately to signals or defects in autoantibody production. Imbalances in cytokines, such as tumor necrosis factor and interleukin, can derail the immune system.

two major adaptive approaches

cellular and humoral immunity key cells involved in these approaches: T cells and B cells

process of chronic inflammation

consists of infiltration with monocyte macrophages and lymphocytes neutrophil and monocyte macrophages continue to cleanup granulomas, which consist of macrophages and lymphocytes, develop in an attempt to separate and contain the infection

live, attenuated vaccines

created from weakened wild viruses or bacteria that can replicate without causing diseases create almost an identical immune response as active infection tend to give longer immune protection; however, oral versions may not give as long-term protection some people don't respond to one dose of a live vaccine, so multiple doses need to be given can cause infections and are contraindicated in those who are immunocompromised fragile and must be protected from heat and light and stored properly

2 major actions of immune system to provide protection

defending and attacking

cellular immunity

defense approach mediated by T cells

effector killer cells (cytotoxic cells)

destroy cells infected with viruses by releasing lymphokines that degrade cell walls marked by CD8+ protein on their surface

immune senescence

deterioration of immune system as a result of aging reduced production of T and B cells altered functioning of mature lymphocytes hematopoietic stem cells that differentiate into lymphocytes are fewer B and T cells proliferate less apoptosis rates are higher thymus gland involutes affecting T cell maturation beneficial cytokine production decreases B cells have decreased capacity to produce immunoglobulins

recombinant vaccines

developed through genetic engineering technology and can include the use of the pathogen's DNA, genetic medication of a pathogen, and a viral vector which is a virus that has been modified to insert genetic material into cells

systemic response of acute inflammation

development of fever, elevated WBCs, release of acute phase proteins pyrogens are molecules that cause systemic response of fever and are either endogenous (interleukin or prostaglandin E2) or exogenous (pathogens) endogenous pyrogens cause fever in response to a pathogen or even in the absence of pathogen

how do B cells work

each B cell has receptor sites for a specific antigen, when it encounters this antigen the B cell becomes activated and multiplies into either plasma cells or memory cells the antibody-producing cells produce millions of antibody molecules during their 24 hour life span B cells can begin this antibody production within 72 hours after initial antigen exposure

fractional vaccines

either toxoid or subunit 3 types of subunits: protein based, polysaccharide and conjugate based

innate immunity - barriers

first innate (nonspecific approach) relies on physical and chemical barriers that indiscriminately protect against all invaders most prominent barriers: skin and mucous membranes

innate immunity

immediate protection, nonspecific, provides protection against all invaders

vasoconstriction and vasodilation of blood vessels

immediately after injury, arterioles in area of injury briefly spasm and constrict to limit bleeding and extent of injury brief vasoconstriction is immediately followed by vasodilation- increases blood flow to area in an attempt to dilute toxins and provide area with essential immune cells (mostly neutrophils), nutrients and oxygen vasodilation also increases permeability which leads to edema As permeability increases, leukocytes line the vessel wall in preparation for migration into the surrounding tissue. While the leukocytes are lining the vessel walls and accumulating (i.e., margination), endothelial cells in the vessel walls react to biochemical mediators that cause these vessels to retract. This retraction gives the leukocytes enough room to migrate (i.e., transmigration) into the interstitial space and begin the cleanup process of phagocytosis, or the engulfing and digestion of foreign substances and cellular debris.

active acquired immunity

immunity gained by actively engaging with antigen- through invasion or vaccination the body makes antibodies and protection is usually long term ex: getting chickenpox and not getting it again or when a person gets the vaccine and never gets chickenpox

passive acquired immunity

immunity gained by receiving antibodies made outside the body or by another person, animal or recombinant DNA person is not actively producing antibodies and protection is short lived ex: mother to fetus placenta, breastfeeding

plasma protein mediators

in addition to cellular mediators, proteins are part of the inflammatory response and are continuously circulating within the plasma proteins are part of 3 systems: complement, clotting and kinins

where are T cells produced

in the bone marrow, but enter the bloodstream and travel to thymus for maturation

subunit vaccines

made from antigenic part of a pathogen (purified antigen) as opposed to the whole pathogen that has been killed subunits can be protein based by using a protein component to present the antigen Other subunits are only made from the polysaccharide wall that surrounds some bacteria (e.g., pneumococcus, meningococcal bacteria). The third type of fractional subunit vaccine are those made by conjugating a piece of the polysaccharide wall with a protein carrier (e.g., Haemophilus influenzae type b, meningococcal vaccine, or pneumococcal vaccine). The pure, polysaccharide (i.e., carbohydrate) -only based vaccines tend to be less effective than live vaccines or inactivated vaccines with a protein base. Additionally, the polysaccharide vaccines are often not very immunogenic. Children younger than 2 years do not respond consistently to these types of vaccines due to their immature immune systems, and these vaccines are, therefore, not effective or recommended in the young. An example is the pneumococcal polysaccharide vaccine 23, which is recommended after the age of 2. The antibody produced with polysaccharides is mainly IgM, which does not confer long-term protection. Inactivated vaccines do not cause disease from infection even in immunocompromised people.

inactivated vaccines

made from whole or fractions of viruses or bacterial antigen or the toxin produced by bacteria response is mainly humoral with little or no stimulation of cellular immunity organisms with inactivated vaccines do not replicate and multiple doses and boosters are usually necessary

normal flora

microorganisms participate in innate immunity to benefit humans bacteria and fungi in skin, GI, GU: normal flora does not cause disease unless imbalance or immunocompromise contribute by: secreting chemicals, blocking pathogenic attachment, and secreting protein molecules

acute tissue rejection

most common and treatable type of rejection These reactions usually occur between 4 days and 3 months following the transplant. Acute reactions are cell mediated with mainly Th 1 cells producing interleukin 2 and interferon gamma, causing macrophage stimulation and resulting in transplant cell destruction (lyses) or necrosis. The patient exhibits manifestations of the inflammatory process including fever, redness, swelling, and tenderness at the graft site. Additionally, the patient may experience impaired functioning of the transplanted organ.

newborns

normal term newborns have maternal antibodies, specifically IgG around 3 months, maternal IgG drops and infant produces own but levels are low until 6 months when production becomes adequate so 3-6 months more susceptible to infections

hyperacute tissue rejections

occur immediately to 3 days after transplant occur due to complement response in which the recipient has antibodies against donor tissue this complement response triggers a systemic inflammatory reaction, so quick that often tissue hasn't had the chance to establish vascularization and becomes permanently necrotic

chronic phase of the inflammatory response

occurs because acute response was not effective in eliminating or repairing injury or infection under certain circumstances, microorganisms are resistant to phagocytosis or even live within macrophages some organisms release toxins that remain after their death

central tolerance and peripheral tolerance

occurs in primary lymphoid tissue (thymus for T cells and bone marrow for B cells) when lymphocytes are maturing with central tolerance, B or T cells that are autoreactive (bind to self) are destroyed or suppressed In the secondary lymphoid tissue (e.g., lymph nodes, spleen) where B and T cells migrate, peripheral tolerance and self-antigens are simply not recognized. With a healthy immune system, self-recognition and tolerance are important mechanisms in shaping the adaptive immune system and maintainence as apoptotic cells and tissue debris needs to be removed. In addition to tolerance, self-antigens are often sequestered, and the immune system has regulatory mechanisms (e.g., B and T cells, cytokines) that limit the degree of immune reactivity.

During the acute inflammatory process, the complement system and interleukin along with other mediators stimulates the bone marrow to produce more leukocytes, particularly neutrophils what do neutrophils do?

phagocytize, release antimicrobials and release their nucleus content to form traps to destroy injurious substances such as bacteria immature neutrophils (known as bands) outnumber mature neutrophils

role of the immune system

protecting body against an array of microorganisms (bacteria, viruses, fungi, protozoans, and prions) remove damaged cells destroy cancer cells

toxoid

protein-based vaccines made by modifying toxins produced by some bacteria, the modification does not cause disease

chemical barriers

skin produces slightly acidic substance that inhibits bacterial growth hydrochloric acid in stomach destroys ingested bacteria tears and saliva contain lysozyme that dissolves bacterial cell walls epithelial layers also secrete several proteins known as cathelicidins and defensins that serve as antimicrobials and can stimulate adaptive immune system

mucous membranes

skin protects body from microbe invasions but some passageways (respiratory, GI, and GU tracts) allow direct access to body's interior these passageways are lined with protective mucous membranes that isn't as thick as skin but does provide a moderate layer of protection epithelial cells are constantly turning over and are thereby preventing microorganisms from residing on surfaces of these passageways mechanical was off their surfaces: ex- vomiting is an attempt to remove toxin/microorganism from GI tract

interferons

small proteins released from cells infected by viruses these molecules diffuse from the site of invasion through interstitial tissue and bind to receptors on plasma membranes of uninfected cells binding of interferons to uninfected cells triggers the synthesis of enzymes that inhibit viral replication interferons don't protect cells already infected by a virus but rather stop the spread of the virus to new cells essentially: interferon production is the dying cell's attempt to protect other cells

where are immune cells located?

some immune cells circulate constantly, always on alert for invasion while others remain passively in tissue and organs waiting to be activated

acute inflammatory response

starts immediately after injury and continues until threat is eliminated (usually hours to days)

treatment for transplant rejection

starts with prevention immunosuppressive therapy

interleukins

stimulate fever and neutrophil proliferation cause liver to produce acute phase reactants most common reactants measured in serum to evaluate presence of inflammation: C-reactive protein, fibrinogen, and erythrocyte sedimentation rate

hypersensitivity reactions can also be categorized by the type of antigen the immune system is responding to

such as self antigens (autoimmunity) antigens from another person (alloimmunity) environmental antigens (allergy)

chronic inflammatory response

takes over until healing and repair are complete (usually weeks to months)

in organ transplantation,

the immune system of the host targets the major histocompatibility complex on donor cell surfaces T cells are activated, cytotoxic cells begin destruction, and T cells facilitate B cell antibody production

skin

thick, impermeable layer of epidermal cells overlying a rich vascular layer known as the dermis newly produced skin cells push the dead ones outward while also removing bacteria the dead cells produce a protective, waterproof layer because of the keratin contained in those dead cells