Adaptive Immunity

immune cytokines: IL-1 IL- 22 IL-5 interferon TNF

IL-1 = macrophages to increase Th IL- 22= Th to increase inflammation IL-5= Th to increase eosinophils interferon= defend against tumor cells & virus TNF= inflammation, apoptosis, pyrogen

What is the role of IgE in immunity?

IgE is a class of antibodies whose role is to protect the body from parasites. However, it is most commonly encountered in health care as the primary immunoglobulin responsible for causing allergies and asthma

Passive acquired immunity?

Preformed antibodies are transferred to a donor to the recipient (like immunoglobins for rabies or maternal antibodies passed from placenta to fetus) temporary immunity

cells that provide cell mediated immunity

T cytotoxic cells, T natural killer cells (NK), lymphokine-producing cells, and memory cells are the primary cells that provide cell-mediated immunity.

What is immunogenicity? How can a hapten become immunogenic?

The ability of an antigen to elicit an immune response is called immunogenicity and includes not only antigen characteristics but also host factors. A small molecule that reacts with a specific antibody but cannot induce the formation of antibodies unless bound to a carrier protein or other large antigenic molecule.

Somatic recombination

This incredible diversity is created by the rearrangement of DNA during T- and B-cell development (somatic recombination) so that each lymphocyte has the ability to recognize only one antigen.

What is active acquired immunity?

an antigen elicits a lymphocyte response. Vaccination provides a common form or intentional active immunity. * produced after natural exposure to an antigen or by immunization Long lived immunity

generation of clonal diversity vs. clonal selection: purpose when/ where does it occur antigen involved final product

clonal diversity= produces large # of T &B lymphocytes with a lot of diversity for antigen receptors. Occurs in fetus, in thymus (T) and bone marrow (B). Produces immuncocompetent T &B cells that can react with antigen (that it has not yet met) and it migrates to secondary lymphoid organs to wait to antigen to come along. Clonal selection= Purpose is to select, expand, and differentiate clones of T&B cells against a specific antigen. Occurs after birth and onward, in the peripheral lymphoid organs (lymph nodes, spleen, other). Produces plasma cells that make antibodies, effector T, helper T, cytotoxic T; regulatory T and memory B &T cells

Three antigen presenting molecules: Where are they found and what do they present?

Class 1 MHC - Found on all cells except RBCs. Important in transplants. Present intracellular antigens. Reacts with Tc (cytotoxic T). Class 2 MHC- found on B cells, some epithelial cells, and (B-lymphocytes, macrophages and certain dendritic cells). Presents extracellular antigens. Reacts with helper T cells (Th) CD1 - Found in B cells, dendritic cells, macrophages, and thymus cells. Presents glycolipids and lipoproteins found in mycobacteria.

What are the major components of the MHC?

Class I MHC molecules are composed of two polypeptide chains, a long α chain and a short β chain called β2-microglobulin Class II MHC molecules are composed of two polypeptide chains an α and a β chain of approximately equal length

clonal deletion

Clonal diversity includes the generation of some T lymphocytes that have the ability to recognize self-antigens. Removal of specific self-reactive lymphocytes is called central tolerance and occurs in the thymus via the process of negative selection, or clonal deletion. This process is achieved through induction of apoptosis in self-reactive lymphocytes.

Extracellular antigens vs. intracellular antigens

Extracellular (exogenous) antigens — antigens that are outside the cell and require phagocytes to ingest them before they can be presented to the immune system. Examples include toxins, allergens, infectious organisms, and drugs. Intracellular (endogenous) antigens — antigens that are found within the body's own cells due to changes in the intracellular environment or the DNA. Examples include intracellular infections and malignancy.

Why is clonal deletion important?

If central or peripheral tolerance is not adequate, autoimmune (hypersensitivity) disorders can result

How are intracellular antigens processed?

In cells that have had intracellular transformation by intracellular infection or malignancy, endogenous antigens are fragmented is and transported to the endoplasmic reticulum. In the endoplasmic reticulum, endogenous antigen fragments are assembled with MHC I molecules and then transported through the Golgi apparatus to the surface of the cell.

What happens during T-cell activation and the cellular immune response?

T cells originate in the bone marrow. Unlike B cells, they then travel to the thymus gland for completion of their maturation process under the influence of thymic hormones. While in the thymus, T cells develop TCRs on their surfaces that determine their antigen specificity and differentiate into two major types of T cells, T helper and T cytotoxic cells. Additional T cells include T regulatory and T memory cells

What role do activated macrophages play in cellular immunity?

T helper 1 cells release interferon γ, which stimulates macrophages to be more effective as APCs. It increases the presentation of antigen on MHC molecules on the surface of macrophages and appears to improve macrophage phagocytosis of foreign invaders. Interferon γ can also be released from T cytotoxic cells, which then helps to activate more macrophages.

What is the T-cell receptor complex?

T lymphocytes recognize and bind antigen via a surface receptor called the T-cell receptor complex (TCR). This receptor is highly specific for antigen. the TCR is bound to the T lymphocyte membrane in association with a different type of molecule called CD3 that provides intracellular communication to the nucleus of the T lymphocyte.

What is clonal selection?

The clonal selection theory explains how the body has an inherent ability to produce an immense diversity of antibodies with different amino acid sequences that are able to bind an enormous range of antigens.

use of monoclonal antibodies

asthma, allergen, cancer, block platelets (prevent clots), block inflammatory mediators (RA, psoriasis, IBS), prevent transplant rejection

What does activation of T and B lymphocytes require

Activation of T and B lymphocytes requires antigen binding to the TCR and BCR with associated intracellular communication; It also requires the interaction of other cell surface molecules such as CD4, CD8, costimulatory molecules, and adhesion molecules.

What is an antigen, and what are self and non-self antigens?

"self" by recognizing molecules on the surface of cells called major histocompatibility antigens. non-self" by detecting foreign antigens on invaders such as bacteria or viruses (infections), antigens on pollens and medications (pollen), antigens on cancer cells, and antigens on cells from another person (transplants).

Criteria to influence the degree to which an antigen is immunogenic

* foreignness to host * appropriate size (larger better) *having adequate chemical complexity *being present in sufficient quantity (too high or too low = tolerance)

There are three molecules that can recognize antigens:

1) circulating antibodies 2) antigen receptors on B cells called B cell receptors (BCR) and 3) T cell receptors (TCR).

What happens during B-cell activation and the humoral immune response?

1st exposure: relatively slow to react to the first (primary) antigen exposure because it takes several days for B- or T-cell clones to proliferate 2nd exposure: primed" for another (secondary) exposure to that same antigen because of the presence of long-lived B and T memory cells that were created in response to the primary antigen exposure. The secondary immune response is faster, with higher antibody titers and more vigorous cell-mediated immunity.

What is an antigen? What is an epitope?

A molecule that can bind with specialized receptors on lymphocytes or with circulating antibodies. The ability of antigen to bind to immune receptors is called antigenicity and is dependent solely on its chemical characteristics. The part of the antigen that can initiate an immune response through lymphocyte binding is called the epitope. (aka antigenetic determinant)

How do T cytotoxic cells kill abnormal cells?

After binding, T cytotoxic cells release perforin, which penetrates and destroys the target cell membrane In addition, T cytotoxic cells can cause the target cells to undergo apoptosis (programmed cell death) Once stimulated by endogenous antigen, T cytotoxic cells are further activated by IL-2 from T helper cells and proliferate to form more T cytotoxic effector cells and to produce T cytotoxic memory cells.

What are antibodies? What are the five classes of antibodies? What is their structure, and how do they bind antigen?

An antibody is glycoprotein produced by plasma cells in response to a challenge by a immunogen. Immunoglobulins (Ig) are commonly called antibodies and include five major classes—IgG, IgM, IgA, IgD, and IgE. IgG constitutes about 80% of the antibodies in the blood and is the most protective against infections. it can cross the placenta and provide immune protection for the fetus. IgA can be divided into two subclasses. IgA1 is found in the blood and IgA2 is found in body secretions. IgA1 is a monomer. IgA2 is called secretory IgA and is a dimer; it protects against penetration of organisms through mucous membranes. IgM is a large pentamer molecule and is produced first in response to antigen to provide the most rapid antibody response to infection. IgD is a molecule found on the surface of immature B cells but its function is still not known. IgE is important in the defense against parasites but unfortunately is most often elevated in allergic disorders.

What are the important steps in B-cell maturation?

B cells mature in the bone marrow by acquiring specific membrane-bound antigen receptors on their surface called B-cell receptors, or BCRs. The random combination of numerous gene products results in trillions of B cells, each with a unique antigen receptor resulting in B-cell clonal diversity. When a B cell finds and binds to its unique antigen, the result is clonal selection. During this process, the B cell becomes activated to proliferate and differentiate into two major cell types—plasma cells that can excrete immunoglobulins and memory cells that will remain in the system for long periods in order to confer long-lasting immunity to that antigen.

What is the B-cell receptor complex?

B lymphocytes also can bind antigen that is circulating in blood or lymph via the B-cell receptor complex (BCR). The BCRs have associated molecules (Ig-alpha and Ig-beta) that can communicate between the surface receptor and the B lymphocyte cytoplasm and nucleus, so that antigen binding can signal the B cell to mature, become activated, and begin producing antibodies

What is the secretory immune system, and how does it work?

B lymphocytes concentrate in lacrimal glands, salivary glands, and in the lymphoid tissue in the breast, bronchi, intestines, and genitourinary tract. This is called the secretory (mucosal) immune system. The primary function of the immune system is to halt viral and bacterial invasion before local or systemic disease can develop and to prevent a carrier state that may result in the spread of infection to others. IgA is the primary immunoglobulin produced by these B cells and is secreted onto mucosal surfaces and into tears, saliva, breast milk, and sweat. IgA binds to organisms and neutralizes or opsonizes the invader, preventing it from causing infection

important CD molecules

CD3 molecule, which is essential to communication between the TCR and the T cell nucleus, CD4 molecule on T helper cells that binds to MHC II molecules on antigen presenting cells, CD8 receptor on T cytotoxic cells that binds to MHC I molecules.

What is cellular immunity?

Cell-mediated immunity refers to the activity of T cytotoxic cells which can remove invading antigens by destroying infected or damaged ( intracellular infection by virus or cancerous) cells.

What is meant by "generation of clonal diversity"?

Every B or T cell is specific for one antigen, but there are millions of foreign antigens they represent.

What is humoral immunity?

Humoral immunity refers to B-cell activation by an antigen and the subsequent formation of plasma cells that can secrete antibodies (immunoglobulins) that are specific for that same antigen. Antibodies can neutralize or remove invading antigens through several mechanisms.

immune cytokines: IL-4 transforming growth factor colony stimulating factor IL- 2 IL-17

IL-4 = Th - B cells - plasma= Antibody transforming growth factor= Th- decrease macrophages / lymphocytes colony stimulating factor= Th= differentiation of blood cells IL- 2 = Th = T&B IL-17= Th = increase inflammation

What is the role of antigen-presenting cells?

In order for the adaptive immune system be optimally activated, antigen must be processed and presented by either macrophages, dendritic cells, or B lymphocytes. These cells are capable of internalizing the antigen, fragmenting it, and presenting it on the surface in conjunction with specialized surface molecules called major histocompatibility complex (MHC) antigens. The combination of foreign and MHC antigens presented on the surface of APCs allows for full activation of lymphocyte. Antigen-presenting cells interact directly with T lymphocytes

What are the two classes of MHC antigens, and what do they do?

MHC I antigens are on all cells except the red blood cells. They function to identify self from non-self. The genes that determine an individual's MHC antigens are inherited, but the expression of these genes is variable so that no person's MHC anitgens are identical to either parent or any sibling (with the exception of identical twins). MHC I molecules also function to present intracellular antigen to T cytotoxic lymphocytes . The MHC II molecules are present only on macrophages, dendritic cells, and B lymphocytes (because these cells commonly involved with foreign invaders) The primary function of the MHC II antigens is to present extracellular antigens to T helper lymphocytes in order to better induce the adaptive immune response

What are major histocompatability complex (MHC) antigens?

MHC molecules (sometimes called HLA, or human leukocyte antigens) are glycoprotein molecules present on the surface of every cell in the body except red blood cells and allow the immune system to distinguish between self and non-self. Each individual has his or her own unique set of histocompatibility antigens; thus, an individual's immune system will recognize another person's cells as non-self. Primary role : These molecules also play an essential role in presenting antigen to T lymphocytes. There are two classes of MHC molecules, MHC I and MHC II.

What are natural killer cells, and how do they participate in cellular immunity?

Natural killer (NK) cells are a type of T lymphocyte that does not go through the full maturation process. The NK cell does not have the capacity to bind to specific antigens; instead, it detects cell surface chemical changes that commonly occur in infected or malignant cells. This is especially important in malignancy because many cancer cells do not express MHC I molecules with attached antigens and therefore cannot be bound by T cytotoxic cells. Natural killer cells bind to damaged cells via a killer-activating receptor and then kill the target cell by releasing perforin and killing enzymes. NK cells also can bind to the Fc portion of antibodies and kill cells that have been targeted

How are extracellular antigens processed?

Once extracellular (exogenous) antigen is ingested by a macrophage or dendritic cell, the antigen is then fragmented in cytoplasmic lysosomes. MHC I and MHC II molecules are assembled in the endoplasmic reticulum and then are transported to the lysosomes so that they can be combined with the exogenous antigen fragments and then transported to the surface of the macrophage or dendritic cell. Thus the cell presents antigen fragments on both MHC I and MHC II molecules. The macrophage or dendritic cell is now called an antigen-presenting cell, or APC. Thus the foreign antigen (exogenous antigen fragment) is presented to the immune system connected to a self-antigen (MHC molecule). This increases the likelihood that the T lymphocytes will be able to recognize the antigen and be optimally activated to respond. B lymphocytes also can function as antigen-processing and -presenting cells in the same way that macrophages do. However, B cells are not effective phagocytes. They ingest exogenous antigen by first binding to the antigen via their surface antigen-specific receptors, then endocytosing the receptor antigen complex into the cytoplasm where it can be processed and presented. Although B cells are capable of presenting antigen on both MHC I and MHC II molecules, they preferentially present antigen on MHC II molecules.

Why is clonal selection important?

Once foreign antigen is encountered by a lymphocyte, that lymphocyte is stimulated to proliferate in order to provide more cells with that same antigen specificity to help remove the antigen and to create a group of long-lived memory cells that can provide immunologic memory for that antigen.

What are the T helper cell subsets?

Once the T helper cell is activated, it begins to proliferate. T helper cell proliferation results in the generation of four major subsets: T helper memory cells T helper 1 cells IL-2 stimulates T cytotoxic cells to proliferate and attack target cells and to form T cytotoxic memory cells. Interferon stimulates macrophages to increase their phagocytic activity, slow tumor growth, and help curb viral replication. T helper 2 cells IL-4 stimulates B cells to proliferate, then to activate into plasma cells and produce antibodies. It also stimulates the production of B memory cells. IL-5 stimulates eosinophils to proliferate and produce cytokines. T helper 17 cells IL-17, IL-22, and IL-22 which serve to enhance the inflammatory response by promoting neutrophil and macrophage infiltration of tissues and increasing the production of antimicrobial proteins and chemokines by epithelial cells.

What are memory cells?

T and B cells produce memory cells that can 'remember' the invader and activate quickly upon subsequent exposure.

What are the important steps in T- cell maturation?

T cell maturation: Lymphoid stem cells that enter the thymus gain a CD2 molecule. They then gain the TCR and its associated CD3 molecule that is necessary for receptor communication with the cell nucleus. Under the influence of IL-7, T lymphocytes then gain both a CD4 and a CD8 molecule. These "double positive" cells quickly lose one or the other such that they retain either CD4 or CD8, but not both. CD4= Th, MHC 2 CD8 = Tc MHC 1

How do T helper cells interact with APCs?

T helper cell activation occurs in three stages: 1. Binding of the TCR and CD4 molecules to presented antigen on the APC 2. Costimulatory signaling- costimulatory molecules on the T helper cell interact with similar molecules on the APC. 3. Activation by cytokines- final step in activation of the T helper cell occurs through release of cytokines from the APC (IL-1 and IL-12) and through autocrine stimulation by IL-2 released from the T helper cell itself

What are the functions of antibodies?

The primary function of antibodies is to fight infection Antibodies can neutralize bacteria and viruses bind to the bacterial surface and make it easier for phagocytic cells to ingest these bacteria effectively. This is called opsonization. Indirect: antibodies can increase the inflammatory response, such as when a drug binds to a B cell and causes antibodies to be produced.

problems with antigen-antibody complexes

antigen-antibody complexes can be deposited into normal tissues. Inflammatory cell and complement activation in normal tissues can result in significant organ damage.

What are the three types of cells capable of antigen processing and presentation (APCs)?

he three major types of APCs are macrophages, dendritic cells, and B cells.

What are some of the most important cytokines in adaptive immunity?

interleukins (IL; communicate between immune cells), interferons (INF), tumor necrosis factors (TNF) colony-stimulating factor (CSF), transforming growth factor (TGF). These cytokines work by binding to receptors on the surface of cells and initiating intracellular communication, which in turn stimulates the DNA to activate the cell and alter its function

What are the two major lines of differentiation of leukocytes? What are primary and secondary lymphoid tissues?

process by which each T and B lymphocyte gains a receptor that specifically recognizes only one antigen. Primary lymphoid organs :The development of antigen specificity by each lymphocyte occurs in the bone marrow for the B cells and in the thymus for the T cells. These cells then migrate into secondary lymphoid tissues, such as lymph nodes, where they then await exposure to the antigen for which they have the appropriate specific receptor.

How does adaptive immunity differ from inflammation?

specific, it produces memory cells, and it induces a response that provides long-lasting protection from invaders.

Why is determining an individual's MHC (HLA) antigens necessary for organ transplant?

*In transplantation, the MHC antigens are referred to as human leukocyte antigens (HLA). *All transplantations (except for red blood cell transfusions) are characterized by the exposure of donor HLA on the donated tissue to the recipient's immune system. *Recognition of foreign HLA results in a powerful response by the recipient's immune system to reject the donated tissue. * The more differences between the donor and recipient HLA, the more powerful the rejection response. *MHC I molecules are the most important to match, the MHC II less so (but are still very important for bone marrow transplant matching)

What is the general definition of tolerance? Where does an active process occur? Where does the peripheral process occur? What is negative selection?

Tolerance refers to the ability of the adaptive immune system to recognize self-antigens and to suppress immunity to those antigens so that the immune system does not attack itself. This is an active process that occurs via central process (thymus and bone marrow) that removes self-reactive lymphocytes from the system before they mature, and a peripheral process that suppresses the function of any self-reactive lymphocytes that may remain. The central process of removing self-reactive lymphocytes is called negative selection, or clonal deletion.

What are T regulatory cells?

Treg lymphocytes that control and dampen the immune response, maintain immunologic homeostasis, and prevent autoimmunity. These cells are CD4+ and therefore may be a form of T helper cell and are activated by antigen presented on MHC II molecules. These cells produce the immunosuppressive cytokines IL-10 and transforming growth factor beta (TGF-beta) which suppress Th1 and Th2 activity, decrease antigen recognition and reduce T helper cell proliferation

What are CD1 molecules

a unique set of molecules on the surface of APCs that can present lipid antigens. (MHC present proteins) This is important in certain infections (e.g., Mycobacterium tuberculosis).