Chapter 21 - The immune system: Adaptive

MHC proteins

(Major histocompatibility complex) Protein on cell surfaces that presnet antigens. Genes of the MHC code for those proteins. No other 2 people code for the same MHCs, only identical twins. Each holds a peptide, either a self-antigen or a foreign antigen. 2 Types: -MHC I -MHC II *RBCs the only non-nucleated cell in our body.

Cytotoxic T cells

(activated CD8) Only T cells taht can directly attack and kill other cells. Roam freely in and out of the blood and lymph and lymphoid organs looking for damaged cells. VIrus infected cells (main target) but also bacterially-infected cells, foreign red cells, transplanted cells and cancer/tumor Lethal hit delivery: 1. TNF (Tumor necrosis factor) Assists in killing tumor cells helps activate macrophages. 2. Perforinsand granzymes: causes target cellto lyse. apoptosis 3. Lymphotoxin: activates enzymes in target cells that causes DNA fragmentation there (NK cells use same mechanisms, they search for abnormalities including lack of MHC I or antibodies coating the target cell. They check for identity flags and T cells check the identity flags.)

Immunological memory

provided by memory cells.

Activation and proliferation of T cells

Can only be activated by APCs, it involves antigen binding and co-stimulation. Typ. happen on the APC surface. Both steps are required for clonal selection. 1. Antigen binding: TCRs (T cell antigen receptors) bind to an antigen-MHC complex on an APC surface and leads to activation. (CD4 and CD8 help bind cells together during antigen recognition) 2. Co-stimulation: T cell stimulated but "idling", needs to bidn to co-stimulatory signals that other moleules on APCs surfaces that are damaged or invaded by pathogens. (w/out it, it could lead to damage to healthy cells). 3. Proliferation and differentiation: Once activated, T cell enlarges and proliferates. This process is promoted by Cytokines released by APCs or T cells. Clones differentiate to perform functions according to their T cell class. Primary response peaks w/in a week, apoptosis bw 7-30 days. Some clones my become memory T cells.

Hodgkin's Lymphoma

Cancer of B cells, can lead to immunodeficiency by depressing lymph node cells.

CD4 and CD8

Cell differentiation glycoproteins are surface receptors but are diff. from T cell antigen receptors. -CD4: typ. become Helper T cells (Th). Help activate B cells, other T cells, and macrophages, and direct the adaptive immune response. (Activated can become a memory T cell) *Some will become regulatory T cells (Treg). Moderate immune response. -CD8: become cytotoxic T cells (Tc). Roam through tissues (specially lymph nodes) to destroy cells in the body that harbor anything foreign, that display the antigenic structure. (Activated can become a memory T cell) -Naive: simply called CD4 or CD8 cells -Activated: called Helper, cytotoxic, regulatory.

Helper T cells

Central role in adaptive immunity (humoral and cellular), they aplify the responses. Help activate B and T cells and induce them to proliferate via interleukins (2 and 4) which activate macrophages and NK cells and help w their proliferation. Their cytokines furnish the chemical help needed to recruit other immune cells. -B cell activation: promote more rapid division, it then signals for antibody formation to egin. -CD8 activation: activate destructive cytotoxic T cells. ***without helper T cells, there is no effective immune response!!!***

Cytokenes

Chemical messengers involved in cellular development, diffrentiation, and responses in the immune system. Include: 1. Interferons: -Alpha and Beta: by many cells, have antiviral effects. Activate NK cells -Gamma: by lymphocytes, activate macrophages. 2. Interleukins: -IL1: released by macrophages. Promotes inflammation and T cell activation, causes fever (Pyrogen). -IL2: by Helper T cells. its liberation is stimulated by IL1 it is a key growth factor. It encourages activated T cells to divide even more rapidly. It also stimulates B cell proliferation, T reg development, and NK cell activation.

Complement fixation and activation

Chief antibody defense used against cellular antigens (bacteria or missmached RBCs). Several antibodies bind close together on the same cell, the complement-binding sites on their stem regions align. It triggers complement fixation into the antigenic cell's surface, follows cell lysis. Also, molecules released during complement activation amiply the inflammatory response and promote phagocytosis via opsonization.

AIDS (Acquired immune deficiency syndrome)

Cripples the immune system by interfering with the activity of helper T cells. It is caused by HIV (Human Immunodeficiency Virus), virus transmitted in body secretions.

Antigen-antibody (immune) complexes

Defense mechanisms used by antibodies include: neutralization, agglutination, precipitation, and complement fixation (The first 2 are the most important). Mostly extracellular although it might get into a cell and help lyse it once it is attached to a virus. PLAN: Precipitation, lysis (by complement), agglutination, and neutralization.

T cell antigen receptors (TCR)

recognize both the "self" antigen and " non-self" antigen. The ones that bind to nonself-self complex triggers multiple intracellular signaling pathways that lead to T cell activation.

Immunotherapy (allergy shots)

Each allergy shot contains a tiny amount of the specific substance or substances that trigger your allergic reactions. These are called allergens. Allergy shots contain just enough allergens to stimulate your immune system — but not enough to cause a full-blown allergic reaction. Each time you make IgM and then IgG, secondary response you make IgM and the lots of IgG. You make enough to be more exposed and destroy them before they cause mast cells release histamine.

Self-tolerance (2)

Each lymphocyte must be relatively unresposive to self-antigens so it does not attack the body's own cell.

Adaptive immune system

Eliminates w nearly equal precisionalmost any type of pathogen. When it fails, diseases such as cancer, AIDS result. It is specific, it is systemic, and it has memory. 2 type of responses: 1. Humoral immunity (antibody-mediated immunity): extracellular targets. It is governed by B lymphocytes. (B cells) 2. Cellular (Cell-mediated immunity):Cellular targets. Governed by various kinds of lymphocytes. (T cells)

Organ transplants and rejection

Even though most transplants are allografts, the recipients immune system (mainly CD8) is attempting to destroy the foreign tissue. To prevent rejection, match donor organ and recipient by ABO blood typing and tissue (HLA/MHC) typing, a minimun of 75% MHC is required. Immunosuppressive therapy is given after transplant, inlcuding cytotoxic drugs. (These will kill immune cells so they wont reject the transplant, concern about opportunistic infections)

Antibody Classes

Five major immunoglobulin classes: IgM, IgA, IgD, IgG, and IgE on the basis of their C regions in their heavy chains. (MADGE) They all have diff. characteristics, biological roles. and locations in the body. Primary response: IgM, late primary response: IgG, Secondary response: IgG (IgM, IgA, IgE switching can occur too)

Dendritic cells

Found at the body's frontiers.They internalize/phagocytize (engulf antignes) They are displayed on the MHCII proteins of cells and enter the nearby lymphatics to get to a lymph node where they will present the antigen to T helper (CD4) cells. They are special, both MHC I and MHC II change when they engulf an antigen. Changes in MHC I present antigen to Cytotoxic T cells (CD8). Now they can go looking for this antigen on MHC I complexes of infected cells.

Competent antigen

Immunogenicity is the ability to stimulate specific lymphocytes to proliferate. Reactivity is the ability to react w the activated lymphocyte and antibodies relased.

SCID (Severe Combined Immunodeficiency syndrome)

It is inherited, dysfunction of B and cells; bubble boy. These children have little to no protection against disease -causing organisms. Successful transplants of matched donor hematopoietic stem cells dramatically improve survival rates.

Autoimmune diseases

Loss ability of immune system to tell "self: from "non-self". The immune system turns against itself. Causes: -Faulty Treg mechanisms -improper maturity of B and T cells that cannot determine self from non-self. Not destroyed during maturation in the thymus or bone marrow and flow freely. -Gene mutation or change in cell structure of "self cells" causes these cells to become immune targets -Foreign Ag may be very similar to some human tissues. Therefore, Ab response would be similar, called cross-reaction. Diseases: -Rheumatoid fever: antibody that reacts to strep bacteria, cross-reacts w endocardium, heart valves, glomerulus and joints. -Rheumatoid arthritis: destroys joints and surrounding connective tissue -Myasthenia gravis: neuromuscular communication impairment, No muscle contraction (flaccid muscles, mostly facial) (B cell) -Myltiple sclerosis: Destroys brain and myelin sheath cells (Tc) -Graves' disease: antibodies have same affect as TSH causing increased thyroxine and hyperthyroidism (Bcell) -Type 1 diabetes mellitus: destroys pancreatic beta cells, resulting in deficit of insulin and inability to use carbohydrates (Tc) -Systemic lupus erythematosus: Destruction of glomeruli, blood vessels, synovial membranes,. Wolf-like red mask. Particulalrly affects the kidneys, heart, lings, and the skin. (B cells) -Glomerulonephritis: Destruction of glomerus (Kidney's flitration memebrane) and impairs renal function. (B cell) *Give medication or train other cells to kill the defective cells. Immunosupresant treatments. Side effects are decreased immune response and opportunistic infections.

Macrophages

Often present antigens to T cells to be activated themselves. Once activated, they are true killers, insatiable phagocytes that also trigger powerful inflammatory responses and recruit additional resources.

Immunocompetence (2)

Part of maturation (2), each lymphocyte must become able to recognize its one specific antigen by binding to it. Once they display a unique receptor on their surface, it is committed to react to one distinct antigenic determinant because all of its antigen receptors are the same. They are activated once they encounter the antigen.

Antigenic determinant

Part of the surface of the Ag on which an Ab can attach or that a lymphcyte can recognize

Class I MHCs

Present on all nucleated cell types except RBCs. Can be altered by intracellular viruses or bacteria or by proteins that are made by cancerous cells. When this happens, these cells are recognized as "non-self" and are destroyed. -Recognized by Naive CD8 Cytotoxic T cells (Tc CD8) -Foreign antigens on MHC are endogenous (intracellular pathogens or proteins made by cancerous cells) -Message: 1. If displayed on an APC: "I belong to self, but have CAPTURED a foreign invader. This is what it looks like. Kill any cell that displays it" 2.If displayed by any other body cell: "I belong to self but have been INVADED or become cancerous. Kill me!"

Immunodeficiencies

Production or function of immune cells, phagocytes or complement are abnormal and results in inability to fight disease, opportunistic infections. -SCID, lymphoma, AIDS

Self antigens

Protein molecule that dot the external surfaces of our cells, not foreign or antigenic to you but strongly antigenic to other individuals (blood transfusion..) Example: MHC

Passive humoral immunity

Ready-made antibodies are introduced into our body.B cells are not challenged by antigens. The protection provided by the "borrowed" antibodies ends when they naturally degrade in the body. Two types: 1. Natural: when the mother's antibodies cross the placenta to the fetus or are ingested by the baby via breast milk 2. Artificial: by administering exogenous antibodies as gamma globulin, harvested from the plasma of an immune donor. They are used to prevent hepatitis A and treat poisonous snake bites (antivenom), botulism, rabies, and tetanus (antitoxin)... the donated antibodies provide immediate protection but the effect is short-lived.

Subacute hypersensitivity

Similar to immediate but has a 3 hour lag time and lasts longer (10-15 hrs vs 1hr) Caused by IgG and IgM. -Cytotoxic (Type II) reactions: antibodies bind to antigens on specific body cells and stimulate phagocytosis and complement-mediated lysis of cellular antigens. Transfusion reaction of mismatched blood and complement lyses the foreign RBCs -Immune-complex (TypeIII) hypersensitivities: antigens are widely distributed and huge number of insoluble antigen-antibody complexes formed cannot be cleared from a particular area + phagocytosis and lots of inflammation. Farmers lungs

Precipitation

Soluble molecules (instead of cells) are cross-linked into large complexes that settle out of solution. Much easier to capture and engulf than freely moving agents.

Developmental immune system

Stem cells of the immune system originate i the liver and spleen during weeks 1-9 of embryonic development. Then the bone marrow takes over. They are born w no immunity and rely on prenatal IgG antibodies from placenta and IgA from breast milk (Passive and natural). Immune system will develop w age and antigen challenges. Immune systems "wear out" w age, probably due to decreased function of lymphocytes and loss of memory cells. Elderly more susceptible to infections. Cancer recognition becomes more difficult.

antigens

substances that can mobilize the adaptive defenses by changing the MHC of a cell. Ultimate targets of all adaptive immune responses. They are large, complex molecules that are not normally present in the body. They are intruders or "nonself" to our immune system. Macrophages, dendritic cells and B cells serve as APC's.

Negative selection (2)

T cells must be able to bind to "self" MHC, but not too tighly! If they bind too tighly they could enhance an autoimmune response. Otherwise it results in apoptosis.

Positive selection (2)

Te cells must recognize self major histocompatibility proteins (self-MHC). Otherwise it results in apoptosis

Leukocyte Antigens (HLA)

The glycoproteins on WBCs that are used in tissue typing for organ donation. (like the AB antigens on RBCs)

Antigenic determinants

The parts of an antigen that are immunogenic.

Receptor diversity

They become immunocompetent before meeting the antigens they may attack later. Our genes, not antigens we encounter, determine which specific foreign substances our immune system will be able to recognize and resist. Somatic recombinantion is a process by which gene segments are shuffled and combined in different ways resulting in the ability to recognize any antigen in will ever encounter.

B cells

They bind to an antigen and process it (do not phagocytize it!) and displayit on their MHC II to the T helper cells. It is activated when matching antigens bind to its surface receptors and crosslink adjacent receptors together.

Exotoxins

Toxic chemicals secreted by bacteria

HIV (Human Immunodeficiency virus)

Transmitted by body secretions (blood, semen, vaginal secretions, saliva and tears). It destroys helper T cells. Cytotoxic T cells and B cells attempt to compensate but cant bc they need Th to be activated. Other cells (macrophages, monocytes, dendritic cells, are known to be infected by the virus also. It results in many opportunistic infections. Treatments: they are aimed at diminishing replication of the viral DNA (Reverse transcriptase inhibitors) or blocking the virus from integrating its DNA into host DNA (integrase inhibitors). They can also interfere with the docking mechanism the virus uses to enter Th cells (fusion inhibitors)

Clonal selection of B cells

they have antigens binding sites that are thought to be the IgD immunoglobulin molecules. Ea. cells has been genetically constructed to recognize a specific antigen structure. They serve as antigen presenting cells (APCs) to helper T cells. They are activated when they bind to an extracellular antigen. They then proliferate and differentiate into plasma cell "clones" (w help of IL2 and 4) which make antibodies, and memory cells which will respond to this antigen if it is encounter again.

Cellular immune response

aka cell mediated immunity. Antibodies are not effective once pathogens get into the cell, it is then when T lymphocytes are involved. They kill body cells if infected by a virus/bac, concerous/abnormal, foreign cells (transplant) Other T cells release chemicals and regulate the immune response.

Hypersensitivities

an abnormal vigorous response to an Ag. The immune system damages tissue as it fights off a perceived threat (such as pollen or animal dander) that would otherwise be harmless to the body. 3 Types: 1. Immediate (antibody associated) 2. Subacute (Antibody associated) 3. Delayed (T cells associated)

Neutralization

antibodies block specific sites on viruses or bacterial exotoxins. The virus/exotoxin cannot bind to receptors on tissue. The antigen-antibody complex is eventually destroyed by phagocytes

Plasma cells

antibody-secreting effector cells of the humoral response. The secreted antibodies (same antigen as the parent) circulate the blood or lyph then bind to free antigens and mark them for destruction by other adaptive/innate mechanisms.

Exogonous antigen

antigens from the outside the cell that have been engulfed by the cells that displays them.

Primary lymphoid organs (2)

thymus and organs. all others are secondary.

Memory cells

clone cells that do not become plasma cells. They can respond almost immediately if they encounter the same antigen.

Regulatory T cells

dampen the immune response. Act either by direct contact or by releasing inhibitory cytokines. They prevent autoimmune reactions by suppressing self-reactive lymphocytes outside the lymphoid organs. Secrete IL-10 and TGF-B which blunt the action of other immune cells. Possible use with autoimmune diseases and transplant rejection. Clinical applications: Transplant rejection, immunodeficiencies, autoimmune diseases, hypersensitivities.

Antigen-Presenting Cells (APCs)

engulf antigens and then present fragments of them, like signal flags on their own surfaces where T cells can recognize them. Naive T cells can only be activated by antigens that are presented on them on MHC. They present antigens to the cells that will deal with the antigens. 3 Types: 1. Dendritic cells 2. Macrophages 3. B lymphocytes

Primary immune response

first exposute to a particular antigen. (antigen binding to a recetor on a B lymphocyte, form clones, plasma or memory cells, secrete antibodies.... Secondary response) The antibody group produces first IgM, then IgG in small quantities, production takes 3-5 days, lasts about 10 days.

Endogenous antigens

fragments of proteins synthesized inside the cell.

Active humoral immunity

when B cells encounter antigens and produce antibodies against them. It is acquired in 2 days, 2 types: 1. Naturally acquired: with a bacterial/viral infection. You develop symptoms and suffer. 2. Artificially acquired: when you receive a vaccine and your body makes the antibodies.

Anergy

when a T cell bind to antigen w/out receiving a co-stimulatory signal. The cell becomes tolerant to that antigen and is unable to divide or secrete cytokines.

Incompetent antigen (hapten)

when small molecules (peptides, nucleotides, hormones) link up with the body's own proteins. Unless attached to pretin carriers, they have reactivity but no immunogenicity.

Secondary immune response

when someone is reexposed to the same antigen (Clone of identical cells, plasma or memory cells, secrete antibodies). They are faster, more prolonged, and more effective because immune system has been primed to the antigen and sensitized memory cells are already on alert. Small amount of IgM followed by a large amount of IgG. Antibody production takes 2-3 days and can stay high for a long time.

allografts

when transplants are same species but not genetically identical

IgE (Monometer)

-Binds to mast cells or basophils. Antigen binding to its receptor end triggers the cell to release histamine and other chemicals that mediate inflammation and allergic reaction. -Secreted by plasma cells in skin, mucosae of the gastrointestinal and respiratory tracts, and tonsils. -Only traces are found in plasma -Levels rise during severe allergic attacks or chronic parasitic infections of the GI tract. -Secondary response (when switching from IgM)

T lymphocytes

-Cellular immune response -No antibody secretion -Targets intracellular pathogens (virus infected cells) and cancer cells -Matures in Thymus -Effectors are cytotoxic T cells (Tc), Helper T cells (Th), Regulatory T cells Treg) -They form memory cells

IgM (Pentamer)

-First secreted by plasma cells during the primary response (Diagnostically useful, indicates current infection) -Fixes and activates complement -Monomer and pentamer form -Monomer: antigen receptor on B cell surface -Pentamer: circulates blood plasma -Potent agglutinating agent bc of numerous antigen-binding sites. -Biggest in size

IgD (Monomer)

-Found on B cell surface -Functions as B cell antigen receptors (just as IgM)

B lymphocytes

-Humoral response - secretes antibodies - targets extracellular pathogens (bacteria, fungi, parasites, some viruses) -Mature in red bone marrow - Plasma cells are the effectors - Form memory cells

IgG (Monomer)

-Most abundant in plasma (78-85% of circulating antibodies) -Main antibody in late primary and secondary responses. -Readily fixes and activates complement. -Protects against bacteria, viruses, and toxins in the blood and lymph. -Crosses placenta and confers passive immunity from mother to fetus.

IgA (Dimer)

-The dimer, Secretrory IgA, it is found in secretions (saliva, sweat, intestinal juice, and milk) -Helps stop pathogens from attaching to epithelial cell surfaces (including mucous membranes and the epidermis) -Monomers existing limited amount in plasma -Secondary response (when switching from IgG)

3 cell types

1. B cells (b lymphocytes) oversee humoral immunity 2. T cells (T lymphocytes: non-antibody-producing lymphocytes that constitute the cellular arm of adaptive immunity 3. APCs (Antigenic presenting cells) do not respond to specific antigens as lymphocytes do but play an auxiliary role.

Lymphocyte development

1. Origin: both precuross originate in the red bone marrow. 2. Maturation: Lymphocyte precursor destined to be T cells migrate (in blood) to the thymus where it matures and is educated. They develop immunocompetence and self-tolerance. B cells mature in the bone marrow. -Positive selection: Cells unable to recognize self-MHC are eliminated by apoptosis. -Negative selection: If t cells do not recognize self-antigens dislayed on self-MHC they pass, if they do, they are eliminated by apoptosis. 3. Seeding secondary lymphoid organs and circulation: Immucompetent but still naive lymphocytes leave the thymus and bone marrow. They "seed" the secondary lymphoid organs and circulate through blood and lymph. 4. Antigen encounter and activation: when a lymphocyt's antigen receptors binds its antigen, that lymphocyte can be activated. 5. Proliferation and differentiation: activated lymphocytes proliferate (multiply) and then differentiate into effector cells and memory cells. Memory cells and effector T cell circulate continuously in the blood and lymph and throughout the secondary lymphoid organs. *1st, naive, don't know what they are doing, thymus teaches the how to recognize specific antigens. As we get older and our T cells get educated, our Thymus deteriorates.

Vaccines

most contain pathogens that are dead or attenuated. Their weakened antigens provide functional antigenic determinants that are both immunogenic and reactive. They also spare us most of the symptoms and discomfort of the disease that would otherwise occur during the primary response. They work on the primary/secondary responses.

Antibodies

Aka Immunoglobulins (Igs) constitute the gamma globulin part of blood proteins. Secreted in response to an antigen by effector B cells called plasma cells and the antibodies bind specifically with that antigen. Structure: -Antibody monomer: 4 chains combined form a molecule. T or Y shaped. -Constant (C) region: same for all antibodies of the same class. (w/ light and heavy chain regions) -Variable (V) region: it binds to specific antigens (w/ light and heavy chain regions) -They can inactivate antigens and tag them for destruction but cannot destroy them. *One unique B cell w/ a unique variable region for every pathogen we ever encounter.

Immediate (anaphaylaxis) hypersensitivity

Aka acute or type I hypersensitivities.It is IgE mediated, can be mild (runny nose, itchy eyes) or severe (asthma attack or anaphylactic shock). Mast cells (tissues) or basophils (blood) secrete histamines for inflammatory response. It causes blood vessel dilation and become leaky (runny nose, itching reddened skin (hives), and watery eyes). Treated w antihistamines or immunotherapy (allergy shots)

Hummoral immunity

Aka antibody mediated immunity. B lymphocytes differentiate into plasma cells which produce antibodies that aid in the destruction of extracellular antigens.Antigen binding is quickly followed by receptor-mediated endocytosis of the cross-linked antigen-receptor complexes. Clonal selection is followed by proliferation and differentiation into effector cells (interactions w T cells are typ. required for B cells full activation.)

antibody

Aka immunoglobulins. A gamma globullin protein molecule that binds to antigens and sets the antigens up to be destroyed.

Class II MHCs

only present on mature B cells, and on APC's (dendritic cells, macrophages, Bcells). When it is altered by the presence of antigenic proteins, the APC is able to present this antigen to T helper cells. -Recognized by naive CD4 and helper T cells (Th CD4) -Foreign antigens on MHC are exogenous (phagocytized extracellular pathogens) -Message: "I belong to self, but have CAPTURED a foreign invader. This is what it looks like. Help me mount a defense against it"

Agglutination

Antibodies have more than one antigen-binding site, they can bind to more than one antigen (cell) at a time. Antigen-antibody complexes can be cross-linked into large lattices. IgM (10 antigen-binding sites) potent agglutinating agent.

Delayed hypersensitivities

Appear in 1-3 days and are T cell mediated. Result in inflammation and tissue damage from citokyine-activated macrophages, and sometimes cytotoxic T cells. Allergic contact dermatitis such as matoux skin test or poison ivy. Tc are doing their job but they are overdoing it!