Immunology: Humoral Immunity

most abundant *complement* protein in plasma

C3 - which is responsible for binding Cd3 to a microbe and activating functions of complement.

X linked hyper IgM syndrome

caused by a mutation in the CD40L gene, located on the x chromosomes, leading to production of nonfunctional forms of CD40L. Much of the serum antibody will be IgM, because of the defective heavy-chain class switching.

Fc receptor

cell surface receptor specific for the carboxyl-terminal constant region of an Ig molecule. These are typically multi chain protein complexes that include signaling components and Ig-binding components. mediate many of the cell-dependent effector functions of antibodies, including phagocytosis of antibody-bound antigens, antigen-induced activation of mast cells, and targeting and activation of NK cells.

follicular helper t cells

cells that accompany b cells back into the follicle of a lymphoid organ and become ______. In response to signals from these molecules, B cells begin to proliferate, forming a germinal center, and the proliferating center B cells undergo extensive somatic mutation of antibody gene variable regions and Ig heavy-chain isotope switching.

membrane attack complex

the end result of complement activation. induce inflammatory responses that also eliminate microbes

the goal of vaccination

to stimulate the development of long-lived plasma cells and memory cells. getting multiple rounds of a vaccination/immunization enhances affinity maturation and therefore, increases the ability of antibodies to bind to and neutralize or eliminate microbes (especially those of a recurrent infection).

secondary antibody response

with protein antigens, secondary responses also show increased heavy-chain isotope switching and affinity maturation, because repeated stimulation by an antigen leads to an increase in the # and activity of helper T lymphocytes

T cell INdepdendent activation of B cells

*polysaccharides, lipids and other nonprotein antigens who produce antibody response without the aid of T cells* relatively simple, don't express a lot of heavy chain isotope switching and affinity maturation. nonprotein antigens, such as polysaccharides and lipids, which can stimulate antibody responses without a requirement for antigen-specific helper T lymphocytes. antigens usually contain multiple identical epitopes that can cross-link membrane Ig on B cells and thereby activate the cells. Humoral immune responses to T-indepdenent antigens show relatively little heavy-chain isotope switching or affinity maturation, two processes that require signals from helper T cells

T cell dependent activation of B cells

*protein antigens, and the antibody responses to these antigens* the more sophisticated and effective of the two responses an antigen that requires both B and helper T cells to stimulate an antibody response. Protein antigens that contain some epitopes recognized by T cells and other epitopes recognized by B cells. Helper T cells produce cytokines and cell surface molecules that stimulate B cell growth and differentiation into antibody-secreting cells. Humoral immune responses to T-dependent antigens are characterized by isotope switching, affinity maturation and memory.

IgM and its effector functions

1. activation of the classical pathway of complement

3 pathways of complement

1. alternative - innate 2. classical - adaptive 3. lectin - innate

Signals required for naive B cell to become activated

1. by antigens binding to membrane Ig

complement activation

1. by microbes in the absence of antibody, as part if the innate immune response to infection 2. by antibodies attached to microbes as part of adaptive immunity

IgE and its effector functions

1. defense against helminths 2. mast cell degranulation (immediate hypersensitivity reactions)

sequence of events in helper t ell-dependent antibody responses

1. independent activation of two cell types by antigen 2. migration of cells toward one another and initial interaction between cells 3. development of extra follicular focus of activated b cells, in which early antibody responses occur 4. formation of germinal centers in which stronger and more effective antibody responses develop

Antibody-mediated opsonization and phagocytosis of microbes (IgG example)

1. opsonization of microbe by IgG 2. binding of opsonized microbes to phagocyte Fc receptors (FcγRI) 3. Fc receptor signals activate phagocyte) 4. phagocytosis of microbe 5. killing of ingested microbe

ADCC

Antibody dependent cellular cytotoxicity; Antibody-coated cells are recognized by NK cells which release cytotoxic granules to kill the cell. Infected cells express microbial proteins on the cell surface. Antibodies bind to these antigens.

IgG and its effector functions

HAVE THE LONGEST HALF LIFE: 3 weeks: protects blood protein 1. neutralization of microbes and toxins 2. opsonization of antigens for phagocytosis by macrophages and neutrophils 3. activation of the classical pathway of complement 4. neonatal immunity: transfer maternal antibody

Steps involved in B cell activation by T cells in the lymph nodes

Helper T lymphocytes that recognize antigen presented by B cells express CD40 ligand (CD40L) and secrete cytokines, which activate the antigen-specific B cells.

FCγRI

High affinity; binds IgG; located on macrophages, neutrophils and eosinophils. function: phagocytosis; activation of phagocytes

Naive B cells express which two classes of membrane bound antibodies?

IgM and IgD - function as receptors for antigens

lectin pathway

NOT initiated by antibodies, but by the attachment of plasma mannose-binding lectin (MBL) to microbes.

Recycling of IgG

Neonatal Fc receptor (FcRn) protects IgG from degradation in lysosomes; Extends half-life; Mechanism utilized in drug design to prolong life of therapeutic agents; Etanercept(Enbrel) (TNF receptor/Fc fusion protein) Treatment for RA

Ways that B cell presents antigen to T cells

The B lymphocytes that bind protein antigens by their membrane Ig antigen receptors endocytose these antigens, process them in endosomal vesicles, and display class II MHC-associated peptides for recognition by CD4+ helper T cells. NOTE: B cells are capable of activating previously differentiated effector T cells, but are inefficient at initiating the responses of naive T cells.

memory cells

a small fraction of b cells differentiate into these. do not secrete antibodies.

classical pathway

activation is triggered when IgM or certain subclasses of IgG bind to antigens.

Define plasma cells.

actively secrete antibodies; the effector cells of humoral immunity

Primary antibody response

amount of antibodies produced after first encounter with antigen are smaller than the amounts produced after repeated immunization

humoral immunity mediated by...

antibodies that bind to extracellular microbes and their toxins, which are neutralized or targeted for destruction by phagocytes and the complement system.

alternative pathway

antibody-independent; occurs when C3b protein binds to microbial cell surfaces. *mediates inflammatory responses to infection as well as direct lysis of microbes.*

complement

collection of plasma proteins that are activated by microbes and by antibodies attached to microbes and function as effector mechanisms of host defense. refers to the ability of these proteins to assist, or complement, the antimicrobial activity of antibodies.

inherited deficiencies of complement proteins

deficiency of c3 results in profound susceptibility to infections

functions of the complement system

elimination of microbes during innate and adaptive immune responses. 1. opsonization and phagocytosis 2. complement-mediated cytolysis 3. stimulation of inflammatory reactions

FCεRI

high affinity; binds IgE; located on mast cells, basophils and eosinophils function: activation (degranulation) of mast cells and basophils

late steps of complement activation

initiated by the binding of c5 to the c5 converts and subsequent proteolysis of c5, generating c5b. the final protein in the pathway, c9, polymerizes to to form a pore in the cell membrane through which water and ions can enter, causing death of the microbe. key component of membrane attack complex.

marginal zone b cells

located in the peripheral region of the splenic white pulp, respond to blood-borne polysaccharide antigens

Fc portion of Ig molecules

made up of heavy chain constant regions; contain the binding sites for Fc receptors on phagocytes and for complement proteins.

net result of early steps of complement

microbes acquire a coat of covalently attached C3b.

IgA and its effector functions

mucosal immunity; secretion of IgA into lumens of GI and respiratory tract; neutralization of microbes and toxins

initial T-B interaction

occurs at the edge of lymphoid follicles, results in the production of low levels of antibodies, which may be of switched isotopes but are generally of low affinity. y

receptor cross linking

occurs when two or more antigen molecules in an aggregate, or repeating epitopes of one antigen molecule, bind to adjacent membrane Ig molecules of a B cell.

Heavy-chain class (isotope) switching

process by which a B lymphocyte changes the class, or isotope of the antibodies it produces, from IgM --> IgG, IgE or IgA, withOUT changing the antigen specificity of the antibody regulated by helper T cell cytokines and Cd40 ligand and involves recombination of B cell VDJ segments with downstream heavy-chain gene segments. in the absence of cd40-cd40l, b cells secrete only IgM and fail to switch to other isotopes. enzyme AID

Plasma cell functions

provide a level of immediate protection if an antigen reenters the body. continue to produce high affinity antibodies; even after the antigen is eliminated.

B-1 cells

respond to nonprotein antigens in the mucosal tissues and peritoneum.

role of antibody regulation in the production of antibodies

secreted antibodies form immune complexes with residual antigen and shut off B cell activation by engaging in inhibitory Fc receptor on B cells.

antibody feedback

serves to terminate humoral immune responses once sufficient quantities of IgG antibodies have been produced.

follicular b cells

the majority of B cells, who reside and circulate through the follicles of lymphoid organs. make up the bulk of T-dependent, class-switched and high affinity antibody responses to protein antigens and give rise to long-lived plasma cells.

opsonins

the molecules that coat microbes and enhance their phagocytosis

opsonization

the process of coating particles for subsequent phagocytosis.

affinity maturation

the process of repeated exposure to a protein antigen that results in the production of antibodies with increasing affinity for the antigen. *leads to the production of antibodies with improved capacity to bind to and neutralize microbes and their toxins.* occurs in the germinal centers of lymphoid follicles and is the result of somatic hypermutation of Ig genes in dividing B cells, followed by the selection of high-affinity B cells by antigen.

Define humoral immunity

the type of adaptive immune response mediated by antibodies produced by B lymphocytes. principal defense mechanism against extracellular microbes and their toxins