Immunology 1

Having undergone initial development, B and T cells leave primary lymphoid organs and travel where?

"Having undergone their initial development, B cells and T cells leave 1° lymphoid organs and "home" to the secondary (2°) lymphoid organs - the spleen, lymph nodes, and mucosa-associated lymphoid tissues (MALT) such as Peyer's patches, tonsils, and the appendix. Recall that 2° lymphoid organs are sites where antigen is brought into contact with lymphocytes in order to induce an immune response (clonal selection). If activated by antigen, a mature B cell proliferates (clonal expansion) and forms a large clone consisting of antibody secreting plasma cells and long-lived memory B cells that have undergone class switching"

Class (isotype) swtich

"Recall that each individual B cell produces antibody of one single specificity that is fixed subsequent to V(D)J rearrangement of heavy and light chain variable region genes. These rearrangements occur prior to exposure to antigen in the early stages of B cell differentiation. However, subsequent to exposure to antigen, a B cell can "switch" to produce different classes of antibody molecules, such as IgG, IgE, and IgA, while still retaining the same antigen specificity. This process, called class switch recombination(CSR), involves further rearrangement of DNA, whereby the same heavy chain VDJ rearranged genes are moved next to a different constant region gene (G, A, or E). It is important to note ONLY the C region is changed, thereby preserving antigen specificity of the B cell.

What are immature B cells?

"The next stage of B cell development is the immature B cell. Immature B cells have now undergone a complete V-J light chain rearrangement, and either kappa or lambda light chains are paired with the μ heavy chain polypeptides. Consequently, immature B cells express membrane IgM. Note that membrane IgM is a monomer, consisting of two heavy chains and two light chains and not the pentameric IgM secreted by plasma cells and found in serum. In the bone marrow, the interaction of a self-antigen with the membrane IgM of an immature B cell results in the death (apoptosis) of that cell. In this way, cells that have created, by random V(D)J recombination, a self-reactive (autoreactive) Ig are removed. This process is referred to as negative selection via "clonal deletion" and is one mechanism underlying immune tolerance.

What are the primary lymphoid organs?

"The primary (1°)lymphoid organs are the sites where lymphocyte development occurs. For B-cells, the 1° lymphoid organ is the bone marrow, whereas, for T cells, the 1° lymphoid organ is the thymus. In the 1° lymphoid organs, lymphocytes develop and express their antigen-specific receptors. Primary lymphoid organs are where Rag1/Rag2-mediated V(D)J recombination creates the enormous diversity of antibodies and T cell receptors (TCR)."

B cell antigen receptor

(BCR) Antibodies on the membrane of B cells function as BCR's. Membrane bound Ig is associated with a signaling molecule consisting of two proteins called Ig alpha and Ig beta.

Natural kill cells

(NK cells) are derived from lymphoid progenitor but are distinct from B and T cells in that they do NOT exhibit antigen specificity. They are large granular lymphocyte-like cells that can destroy virus-infected and tumor cells without prior stimulation.

Key points for secondary lymphoid organs

1) Antigen specific immune responses generated here 2) Contain large numbers of b and t cells 3) spleen 4) Lymph nodes 5) MALT (which includes peer's patches, tonsils, appendix)

Key points of innate immunity

1) First line of defense 2) Broadly specific 3) Always ready to respond (doesn't require prior exposure) 4) No immunological memory- response not enhanced by previous exposure to the pathogen

Two types of adaptive immune responses

1) Humoral 2) Cell-mediated

Two types of immune response:

1) Innate 2) Adaptive

Lymphoid Lineage Cells

1) Lymphocytes which include B and T cells that express antigen-specific receptors and mediate the adaptive (acquired) immune response. Lymphocytes are small cells composed mostly of nucleus with only a thin rim of cytoplasm. 2) NK cells

The major cellular defenses of innate immunity:

1) Phagocytosis 2) Cellular cytotoxicity 3) Mast cell and basophil mediated inflammation

The lymphoid organs are divided into two general categories:

1) Primary 2) Secondary

Key points about primary lymphoid organs

1) where development of lymphocytes occurs and the antigen-specific receptor is acquired 2) B cells- bone marrow, T cells - thymus

Multiple Myeloma

A cancer of a plasma cell (effector B cell). A single plasma cell becomes neoplastic, growing out of control and crowding out the bone marrow. The plasma cells will produce large amounts of specific antibody. This is normal antibody in structure but produced in abnormally large amounts. The antibody produced by the neoplastic cells is monoclonal since it is essentially produced by a single clone. Patients with multiple myeloma will have a very large g-globulin peak. Also patients will have a serum Ig that is either almost 100% k or 100% l.

Describe a secondary antibody response to antigen

A memory response characterized by: a shorter lag phase than the primary response, meaning the time between exposure to antigen and the production of antibodies is less. There is greater increase in specific antibody compared to the primary response. A larger proportion of "switched classes" (IgA, IgG, and IgE) are present. The antibodies of the memory response are of higher affinity than those of the primary response due to somatic hypermutation and selection.

All leukocytes ultimately originate from what?

A pluripotent stem cell. There are two main cell lineages that derive from the common stem cell: the myeloid and the lymphoid lineage.

Class switch recombination and somatic hypermutation both require what enzyme?

AID (activation-induced cytidine deaminase) A defect in AID gene is now known to be responsible for the lack of CSR and SHM in patients having an immunodeficiency disease called Hyper-IgM Syndrome 2. AID is expressed in B cells that are proliferating in the germinal centers of secondary lymphoid tissue (lymph nodes, spleen, tonsils) which is the site of CSR and SHM.

Neutralization:

Antibodies can inactivate toxins, viruses, or prevent bacterial colonization by binding to the toxin or pathogen. A receptor on the virus binds to a molecule on the cell surface to initiate infection. However, if antibody binds the receptor on the virus, the ability of the virus to infect those cells can be blocked and the virus is "neutralized". Similarly, toxins can be neutralized by antibody binding to the part of the toxin molecule needed to bind and enter cells. The process of neutralization generally requires high affinity antibody. IgA and IgG are the most effective neutralizing antibodies.

IgA dimers are found:

As the major secretory immunoglobulin in mucosal secretions. Due to the large SA of mucous membranes, more IgA is produced each day than any other class.

What is the site of origin for all types of blood cells, including leukocytes?

Bone marrow

What are Peyer's patches?

Clusters of lymphocytes distributed along the lining of the small intestine. There are mucosa-associated lymphoid tissues (MALT), gut associated (GALT), and bronchus associated (BALT).

What are pattern recognition receptors?

Dendritic cells, macrophages, and neutrophils have receptors that recognize common features of pathogens. These are called PRR's and the pathogen-associated molecules they recognize are called pathogen associated molecular patterns (PAMPs).

T cells

Do not produce antibodies and can be divided into two sub populations: Cd4+ and CD8+ T cells. CD4 T cells function by secreting cytokines. CD8 cells recognize and destroy infected cells and tumor cells

Humoral immunity

Effector B cells (plasma cells) secrete proteins called antibodies that are soluble and circulate throughout the body to come into contact with and bind antigen. Antibodies bound to antigen then trigger a variety of different antibody effector mechanisms to eliminate the pathogen. Memory B cells are long lived that retain antigen specificity and allow for faster and strong immune response on subsequent antigen exposure. You can measure humoral immunity with serum antibodies.

Cell mediated immunity (CMI)

Effector mechanisms that are mediated by activated T cells (CD4 or CD*). T helper (CD4) function by producing cytokines. Cytotoxic T cells (CD8) function by recognizing and killing pathogen infected cells or tumor cells. IN general, cell-mediated immunity deals with intracellular pathogens such as viruses and some bacteria. Humoral immunity deals with extracellular pathogens (most bacteria and parasites)

Antigens

Foreign substances. Can be carbs, lipids, proteins, and nucleic acids. (lipids and nucleic acids are poor immunogens but when conjugated to proteins can become immunogenic.)

Antibody Structure:

Four chains: Two heavy chains and two light chains. In any one antibody molecule, the two H chains are identical and the to L chains are identical. Each H chain is linked covalently to an L chain by a disulfide bond b/w two cysteine residues. The two H chains also linked this way. An antibody consists of two Fab (fragment antigen binding) regions and one Fc region. The Fc region determines the effector function. The antigen binding site is formed by the VL (variable light chain) and VH (variable heavy chain) domains.

General properties of antibodies

Glycoproteins found in serum, extracellular fluid, and mucosal secretions. They are secreted by effector B cells (plasma cells) in response to antigen. Antibodies are antigen specific. (Immunoglobulins)

Haptens

Haptens are small molecules and include such substances as antibiotics, drugs, and chemicals. By themselves, haptens can't induce an immune response. However, when coupled with a larger molecular weight carrier, usually a protein, the resultant conjugate induces an immune response.

The interactions between an antibody molecule's antigen binding site and antigen involve all of the forces involved in protein-protein interactions:

Hydrogen bonds, hydrophobic interactions, ionic interaction, Van der Waals forces. Strength of interaction b/w the antibody and antigen is referred to as infinity.

What type of antibody is found in submucosal tissues?

IgE (on mast cells)

What kind of antibody is found in the fetus?

IgG (maternal IgG transported across the placenta)

What type of antibody is found in the blood (serum or plasma)

IgG; IgM (pentamer); IgA (mostly monomers)

What kind of antibody is found on B cell membranes?

IgM and IgD on mature B cells; IgG, IgA, or IgE on memory B cells.

How is IgM and IgA found in the body?

IgM is pentameric with a J chain holding the 5 antibodies together. IgA is dimeric or monomeric in the serum. In mucosal secretions, its a dimer. Since the IgM pentamer is very large, it does not pass out of the circulation into body tissues and since each antibody monomer contains two antigen binding sites, an IgM pentamer contains a total of 10 antigen binding sites.

During the early stages of an immune response, plasma cells secrete antibody of what class?

IgM. However, if an activated B cell receives the appropriate signals (cytokines) from T cells, class switching (isotype switching) may occur. During the clonal expansion of this B cell, some of the progeny will "switch" isotypes - that is, begin to produce IgG, or IgE, or IgA. It is important to note that the light chain does not undergo switching and, except for somatic point mutations (somatic hypermutation), remains the same. All of the antibody produced by this clone of B cells will retain the original antigen specificity of the IgM and IgD that was on the membrane of the original mature B cell.

What are mature B cells?

Immature B cells develop into mature B cells that have both membrane IgM and membrane IgD at their cell surface. The antigen specificity of both the IgM and the IgD on the same B cell are identical. This is accomplished by alternative splicing of a single heavy chain RNA transcript containing a unique VDJ rearranged gene unit plus both μ and δ constant region genes. Within the same mature B cell, some of these transcripts are spliced to contain only the μ-constant region sequence whereas others are spliced to contain only the δ-constant region sequence. Mature B cells leave the bone marrow and migrate to secondary lymphoid organs and the circulation in order to seek out foreign antigen. These mature B cells are capable of being activated by antigen to produce plasma cells and memory cells. They are considered naive B cells.

Immunoglobulin Classes (Isotypes)

In mammals, there are five classes based on heavy chain constant region sequences. Each has a different set of biological functions. In humans, there are 4 subclasses of IgG and 2 of IgA.

IgA is also found:

In milk, saliva, and tears

Describe the initial antibody response to antigen

In primary response, the serum antibody specific for the antigen is mostly IgM (although IgG may appear later in response). B cells that recognize the antigen proliferate and subsequently differentiate into antibody secreting cells (plasma cells) and long lived memory B cells.

IgM pentamers are found:

In the bloodstream b/c of their large size

The antibody response:

Initial exposure: primary response Secondary exposure: secondary/memory response

During V(D)J recombination, what is being recombined?

Is is DNA that is actually cut and ligated together during V(D)J recombination. Within the DNA genome, one V segment gene is rearranged with one J segment gene; RNA is then transcribed; introns are spliced out; and the resulting mature mRNA, consisting of V-J-C segments, is translated to a light chain polypeptide.

What is the main goal of class switching?

It allows antibody with a single antigen specificity to be produced in a variety of different classes, thus allowing the antibody response to take on a number of different effector functions. Antibody class determines biological activity of the antibody by determinng the antibody's Fc region.

What is adaptive immunity?

It comes later during the body's immune response, some time after exposure to the invading pathogen. Antigen specific mediated by B and T cells which have antigen-specific receptors on their surfaces. There is immunological memory. Adaptive immunity is also known as acquired immunity.

Mast cell degranulation and antibodies:

Mast cells are cells of the immune system that mediate inflammatory responses via the release of various substances (histamine). IgE mediated mast cell degranulation is important in the protected against parasites, such as helminths (worms), and tends to occur near body surfaces (skin and mucous membranes). Mast cells have Fc receptors that bind IgE. However, in contrast to opsonization and ADCC, mast cell Fc receptors bind IgE before IgE binds to antigen. IgE already bound to Fc receptors on mast cells can then bind antigen. IgE crosslinks activates the mast cell to degranulate.

Myeloid Lineage Cells:

Mast cells, Basophils, Eosinophils, neutrophils, granulocytes, dendritic cells, monocytes, macrophages

Summary of B cell class switching

Mature B cell -> expresses IgM and IgD on surface Upon initial exposure to antigen: Plasma cells -> secrete IgM pentamer (early primary response) Memory cells--> express either IgG or IgE or IgA on cell surface Upon subsequent antigen exposure: Plasma cells secrete IgG or IgE or IgA (secondary response)

Production of IgM and IgD by the same B cell

Mature B cells express both IgM and IgD on their membranes. Both IgM and IgD molecules expressed by an individual B cell have identical antigen specificities and thus recognize the same antigen. This is because only the heavy chain constant region differs between the IgM and IgD molecules.

How are the innate and acquired immune responses interdependent?

Mechanisms of innate immunity produce signals (usually cytokines) that stimulate and direct the subsequent adaptive immune response. Conversely, the adaptive immune response generates signals that stimulate and direct mechanisms of innate immunity.

How is class switch affected by T cells?

Membrane proteins on T cells deliver signals. Also, T cells direct B cells to switch to a particular heavy chain class by the particular cytokines they secrete. Cytokines are small soluble proteins produced by one cell that affect the behavior of other cells. Cytokines are key elements of both innate and adaptive immune responses.

Light chain isotopes:

Most species produce two isotopes of Ig light chains: kappa and lambda. In humans, 60% of antibodies have k chains and 40% have l light chains.

Antibody-dependent cell-mediated cytotoxicity (ADCC)

Natural killer cells are an important component of innate immunity and function to kill some, although not all, tumor cells and cells infected by viruses or intracellular bacteria. NK cells are not antigen specific. The killing mechanism used by NK cells involves the transfer of enzymes to the target cell and induction of target cell apoptosis. ADCC is an example of how antibodies can enhance an innate effector function. NK cells have Fc Receptors that recognizes antibody bound pathogens coated with IgG and the NK cells will eliminate these aberrant cells.

Recruitment of leukocytes to sites of infection

Neutrophils and monocytes are recruited from the blood to sites of infection by chemokine produced in response to infection. Resident dendritic cells and tissue macrophages that recognize microbes secrete the cytokines TNF, IL-1, and IL6 that act on the endothelial cells and induce expression of several adhesion molecules. Cheekiness then act on adherent leukocyte and stimulate the cells to migrate through the inter endothelial spaces toward the function. The net result is that neutrophils and then monocytes rapidly accumulate around the infectious microbes.

B lymphocytes originate from what kind of cells?

Pluripotent (multipotential) stem cells in the bone marrow. Stem cells are cells which are capable of developing into any of the many hematopoietic cell types. In humans, bone marrow is the primary site of B cell development throughout life.

Phagocytosis

Process whereby specialized cells of the immune system ingest and then destroy invading microorganisms, such as bacteria. The major phagocytes are neutrophils and macrophages.

What two genes are expressed exclusively in developing lymphocytes and are required for the initial cutting of the Ig or TCR genes?

RAG-1 and RAG-2. They are critical for the development of both B and T cells. In the absence of these genes, no B or T cells are produced. A defective RAG 1 or RAG 2 gene is one etiology for severe combined immune deficiency.

Plasma cells:

Recognition of antigen by a mature B cell will cause that B cell to proliferate. Activated B cells can differentiate into plasma cells that synthesize and secrete large amounts of antibody. They do not express surface Ig.

What type of antibody is found on mucosal surfaces/secretions?

Secretory IgA (IgA dimers plus secretory componente)

Heavy chain gene rearrangment

Similar to light chain rearrangment. One difference is that in addition to V and J segments, genes coding for the variable region of antibody heavy chains include diversity (D) segments. Thus, the variable region of the heavy chain is coded for by THREE gene segments: V, D and J. As a result, TWO rearrangements of DNA must occur. 1) One D segment and one J segment come together 2) Then one V segment joins the D-J segment to make a complete VDJ gene unit. A second difference is the presence of multiple gene coding for the constant region of the heavy chain in the heavy chain Ig locus. The constant region genes closest to the variable region Cmu and Cdelta, corresponding to the IgM an IgD heavy chain content regions. After VDJ gene unit has been constructed, this rearranged DNA is then transcribed along with the two closest C regions (IgM and IgD). The resulting primary transcript can be spliced in two alternative ways to yield either VDJ IgM or VDJ IgD when can then be translated to IgM or IgD heavy chains. The resultant B cell may express both antibodies with identical antigen specificity. The other constant region genes (gamma, alpha, and epsilon for IgG, IgA, and IgE) can be expressed after following class switch recombination.

Secondary lymphoid organs

Sites where lymphocytes encounter and respond to antigens. Mature B and T cells migrate from the bone marrow and thymus through the bloodstream to secondary lymphoid tissues. These sites are designed to trap antigen and facilitate antigen contact with lymphocytes. Recognition of antigen by lymphocytes drives proliferation and differentiation of B cells and T cells, initiating an immune response.

What are lymph nodes?

Small structures that occur along lymphatic vessels. In lymph nodes and the spleen, antigen stimulates the expansion of antigen specific B and T cells. Lymph nodes filter lymphatic fluid for antigens (the spleen filters blood for antigens).

What are the two major systemic secondary lymphoid organs?

Spleen and lymph nodes

Opsonization

The coating of a microbe or other particle with a substance that makes the microbe more readily phagocytosed. IgG is an important opsonin. Phagocytic cells (macrophages and neutrophils) have Fc receptors that bind the Fc regions of antibodies. As a result, these cells will recognize and ingest antibody coated pathogens.

Activation of the complement system

The complement system is a series of proteins that mediates a host defense against various extracellular pathogens, especially bacteria. One effect of the complement system is to amplify the inflammatory response. Complement releases chemotactic factors that direct the migration of phagocytic cells towards the site of complement activation. Another function of complement proteins is to form pores in bacteria cell walls and membranes, causing the bacteria to swell with fluid and burst. Both IgG and IgM antibodies can activate the complement system.

Summary of V(D)J rearrangement:

The constant regions of Ig chains, both heavy and light chains, are encoded by C genes. Complete Ig light chains (Ig lambda and Ig kappa) are encoded by V, J, and C genes whereas heavy chains are encoded by V, D, J, and C genes. This allows for the creation of different antibody sequences from sets of genes encoded with the heavy and light chain Ig loci.

Variable and constant regions

The domain at the N terminus in both heavy and light chains is extremely variable in amino acid sequence amongst different antibodies. These domains are called variable regions (V regions): VH and VL. The other remaining domains of each chain form the constant regions (CH AND CL). The variable regions are where antigen specificity resides. Cleavage of an antibody molecule at the hinge region results in two Fab fragments, which bind antigen, and one Fc fragment.

Primary response vs memory response

The first exposure to antigen results in activation of naive B cells which allows for plasma and memory cells to be generated. In subsequent responses, (secondary responses) the presence of an expanded population of memory B cells results in a more rapid and robust humoral immune response.

Hematopoiesis

The generation of the cellular components of blood: red blood cells, white blood cells, and platelets. White blood cells (leukocytes) are the blood cells which function in immunity.

Brief description of V(D)J recombination

The human body can produce billions of different B and T cell receptors using a set of genes numbering only in the hundreds. This is accomplished by recombining Ig and TCR genes in a variety of different ways to produce enormous diversity of receptors in the immune system. In this way, the immune system can generate a large number of lymphocyte receptors necessary to cope with the universe of pathogens. The Ig and TCR genes actually move and rearrange themselves within the genome of developing lymphocytes. The mechanism by which lymphocytes create unique antigen-specific receptors is called V(D)J recombination.

The Clonal Selection Theory

The immune system is comprised of many different lymphocytes. Each individual lymphocyte is specific for a single antigen. Each lymphocyte has a unique surface receptor for antigen. Only a small number of lymphocytes will recognized a particular antigen. Recognition of antigen signals the cell to proliferate. This clonal expansion results in a large clone of cells, all expressing receptors that recognize the same antigen. Proliferating lymphocytes eventually differentiate into effector cells or memory cells. (Both B and T cells)

What is innate immunity?

The initial response that the body mounts against an invading pathogen. It's always present and mounts a rapid response. examples include: Physical barriers such as skin and mucous membranes, chemical defenses such as highly acidic environment of the stomach, antimicrobial agents like lysozyme in saliva and tears, and cellular defenses like phagocytosis and cellular cytotoxicity.

Light chain gene rearrangement

There are two isotopes of antibody light chain, kappa and lambda. Each consists of a constant region and a variable region. The variable region of the light chain is coded for by TWO separate gene segments: a variable (V) segment and a small joining (J) segment. One V segment and one J segment gene come together in the genome of a differentiating B lymphocyte to create a complex V-J gene unit that, together with the C region gene, codes for an entire antibody light chain.

What are pre-B cells?

They have undergone a complete V-D-J segment heavy chain rearrangement. This rearranged heavy chain V-D-J unit is located adjacent to the Cμ gene, and the pre-B cell produces a μ heavy chain polypeptide. However, light chain rearrangement has not occurred and neither kappa nor lambda light chains are produced at this stage. Without light chains, the μ-chain cannot form IgM molecules.

After differentiation, B cells first produce IgM and IgD antibodies. Why?

This is because Cmu and Cbeta are the first gene segments in the constant region immediately after the variable region in rearranging DNA. RNA transcripts are then made with both the m and d segments included. Using a processed called alternative RNA splicing, splicing of the primary RNA transcripts at different sites produces mature messenger RNAs with either Cmu or Cdelta segment but not both. The resulting mu chain and delta chains retain the exact same VDJ rearranged variable region genes and thus will have the same antigen binding site.

What is the PRR that recognizes endotoxin (LPS) from gram-negative bacteria?

Toll like receptor 4 (TLR4). LPS is the PAMP recognized by TLR4 the PRR.

Secondary lymphoid tissues associated with mucosal surfaces include:

Tonsils, appendix, and Peyer's patches

The generation of diversity of antigen-specific receptors on both B and T lymphocytes uses what mechanism?

V(D)J recominbation

Secretory IgA needs to pass across epithelial cells to reach mucosal surfaces or enter secretions. How is this achieved?

When dimeric IgA binds the polymeric Ig receptor at the basolateral membrane, it is internalized and transported across the cell through the cytoplasm (transcytosis). The dimeric IgA is then released from the apical surface of the cell onto the muosa. During this process, the IgA dimer covalently binds to the pIgR. The release of the IgA dimer is mediated by enzymatic cleavage of the pIgR at the apical surface of the epithelial cell. Following this cleavage, part of the pIgR remains bound to the IgA dimer. This remaining fragment is called secretory component, which is thought to make IgA more stable within the external environment. Dimeric IgA with SC is called secretory IgA.

Mast cell and basophil mediated inflammation

When mast cells (in tissue) and basophils (in blood) are activated they release histamine and other soluble mediators to produce an inflammatory reaction. This response evolved primarily as a defense against parasitic infections (worms)

Cellular cytotoxicity (killing)

a process which involves killing of abnormal human cells, such as virally infected or tumor cells. Altered features of the membranes of the abnormal cells are recognized by certain cells of the immune system and then biologically potent molecules are released that kill the abnormal cell. (Natural killer cells)

IgG is the major immunoglobulin in:

blood and tissues. Because IgG is present in monomers, it can diffuse out of capillaries into adjacent tissues.

While individual mature B cells can produce both IgM and IgD on their cell surfaces, after class switching, an individual B cell

can only produce ONE of the switched isotopes (IgG, IgE, or IgA)

Basophils

circulate in the blood and are thought to have a function similar to mast cells

Mast cells:

congregate in tissues and release various soluble mediators such as histamine when activated. They play a major role in allergic responses (also in worm defense)

Dendritic cells

found in most tissues, including the lymphoid tissue. They take up and transport antigen to peripheral lymphoid organs where they function as potent activators of T cells.

Granulocytes

have cytoplasmic granules. these include neutrophils, basophils, and eosionphils. The three cell types were named for the staining properties. Neutrophils stain pale lilac, eosinophils stain red, basophils stain dark blue

Eosinophils

leukocytes important in defense against parasitic infections

Babies are born with:

maternal IgG. IgG is the ONLY antibody class that can cross the placenta. IgG has a half life of 3 weeks. Thus, maternal IgG provides passive immunity to the newborn that is protective for 2-3 months.

Monocytes

phagocytic leukocytes found in the blood. They are precursors to tissue macrophages

Macrophages

phagocytic leukocytes found in tissues. They are derived from blood monocytes. They are given various names depending on the tissue location in the body

Neutrophils

phagocytic leukocytes that have an important role in engulfing and destroying extracellular pathogens, primarily bacteria. Neutrophils are often referred to as polymorphonuclear leukocytes or "polys" due to their multi-lobed nucleus

B cells

produce antibodies which target primarily extracellular pathogens, especially bacteria. Since antibodies circulate in the bloodstream and lymphatic system to target antigens, B cells are said to mediate humoral immunity.

Combinatorial diversity

refers to all the possible combinations of V,D, and J genes that can be produced by VDJ recombination. The different combos in heavy chain rearrangement provide a rich source of diversity. The different combos of heavy and light chains also contributes to diversity. Ex: 6000 different heavy chains can combine with 200 different kappa light chains to create over one million unique antigen binding sites.

Somatic Hypermutation (SHM)

refers to random point mutations that occur in the variable regions of Ig heavy and light chains in the B cells of an expanding clone. Generally, an antibody of relatively low affinity is produced during a primary response to antigen. As a B cell response proceeds, an increase in the affinity of antibody for antigen is observed. This increase is mediated by somatic hypermutation. Proliferating B cells have a mechanism which will mutate, at a high rate, the DNA that encodes the variable region of the light chain and the variable region of the heavy chain (i.e. the genes that have undergone V(D)J recombination). This process is referred to as somatic hypermutation because the mutation of DNA occurs at a rate at least 10,000-fold greater than the normal rate of mutation found in most cells. Due to the low concentration of antigen, only those B cells with mutated antibody having higher affinity will be able to bind antigen and continue to be stimulated to proliferate. B cells that no longer bind antigen will die off after a certain period of time. Those B cells that have mutations resulting in a lower affinity for antigen will die off since their BCRs will not be able to "compete" for antigen. **CLONAL SELECTION**

Junctional diversity

refers to the imprecise joining of the V, D an J gene segments during VDJ rearrangement. The joining of VDJ genes during differentiation evolved to be "sloppy". Imprecise DNA recombination can lead to changes in amino acids at these junction sites, adding much additional diversity to the antigen binding site. When gene segments are excised for V(D)J recombination, exonucleasesrandomly "chew back" a variable number of nucleotides from the ends of the joining segments. In addition, an enzyme called terminal deoxynucleotidyl transferase (TdT) randomly adds entirely new nucleotides to the ends of the segments prior to their joining. The net result is that a variable number of nucleotides are deleted from the joining segments and then variable numbers are added back in a random manner. This makes the junctions b/w VD and J gene segments highly variable and extremely important for the creation of diversity at the antigen binding site.

Germline diversity

refers to the multiple different V,D, and J gene segments. In addition, multiple alleles for each of these genes (genetic polymorphism) exist within the population

The part of the antigen that interacts with the antigen binding site on the antibody is called:

the epitope, or antigenic determinant. The epitope is the specific structure on the antigen that is recognized and bound by antibody.

Primary lymphoid organs

the sites of lymphocyte development. In primary lymphoid organs, B and T cells undergo differentiation culminating in the expression of antigen-specific receptors. For B cells, this occurs in bone marrow, for T cells in the thymus.