Biology 151 lecture 4 2012 2013 (part 2 hi)

HUMORAL IMMUNITY

Thursday, July 19, 2012

HUMORAL IMMUNITY• RECALL: mediated by antibodies AND functions to neutralize and eliminate

extracellular microbes and microbial toxins

• e.g. microbes with capsules rich in polysaccharides and lipid toxins

• B-cells respond to and produce antibodies specific for many types of molecules (vs T cells = only protein antigens)

• WHAT ARE WE TO KNOW: process and mechanisms of B-cell activation and antibody production

• How are receptor-expressing B-lymphocytes activated and converted to antibody-secreting cells

• How is the process of B-cell activation regulated so that the most useful types of antibodies are produced in response to different types of microbes

PHASES OF HUMORAL IMMUNE RESPONSES

TD & TI ANTIGENS

TD and TI ANTIBODY RESPONSES

• RECALL: based on the requirement for T-cell help

• T-dependent antibody response: Protein antigens are processed in antigen-presenting cells and recognized by helper T-lymphocytes, which play an important role in B cell activation PLUS powerfuI inducers of heavy chain class switching and affinity maturation

• In the absence of T cell help, protein antigens elicit weak or no antibody responses

• T-independent antibody response: Polysaccharides, lipids, and other nonprotein antigens stimulate antibody production without the involvement of helper T cells

• Antibodies show relatively little heavy chain class switching and affinity maturation

PRIMARY & SECONDARY IMMUNE RESPONSE

So how do antigens stimulate B-lymphocytes?

ANTIGEN RECEPTOR-MEDIATED SIGNAL TRANSDUCTION IN B-LYMPHOCYTES

• RECOGNITION & INITIATION: antigen-specific B-cells in the lymphoid follicles of the spleen, lymph nodes and mucosal lymphoid tissues recognize antigens

• membrane-bound Ig receptors recognize antigen in their “native conformation” (without a need for processing)

• SIGNAL TRANSDUCTION: Antigen-induced clustering of membrane Ig receptors trigger biochemical signals that are transduced by receptor-associated signaling molecules

THR ROLE OF COMPLEMENT PROTEINS IN B-CELL ACTIVATION: C3d (“second signals”)

B-cells express a receptor for a protein of the complement system that provides signals for the activation of the cells

(NOTE: C3d = analogous to co-stimulators of T-cells)

FUNCTIONAL CONSEQUENCES OF Ig-MEDIATED B-CELL ACTIVATION

Note: antigen stimulation induces the early phase of the humoral immune response

= response isgreatest when:a) antigen is multivalent

b) antigen cross-links many antigen receptors

c) antigen activates complement strongly

= typical of polysaccharides and other TI antigens

The Function of Helper T-lymphocytes in Humoral Immune Responses to Protein Antigens

T-CELLS IN B-CELLS FUNCTIONING

•Efficiency: protein antigens elicit excellent antibody responses within 3-7 days of antigen exposure

•Helper T-cells that have been activated to differentiate into effector cells interact with antigen-stimulated B-lymphocytes at the edges of lymphoid follicles in the peripheral lymphoid organs

INTERACTIONS OF T-CELLS & B-CELLS IN LYMPHOID TISSUES

ANTIGEN PRESENTATION BY B-LYMPHOCYTES TO HELPER T-CELLS

B-cells act as APC

HELPER T-CELL-MEDIATED ACTIVATION OF B-LYMPHOCYTES

ISOTYPE SWITCHINGHelper T-cells stimulate the progeny of IgM+ IgD expressing B-lymphocytes to produce antibodies of different heavy chain classes (isotypes) initiated by CD40L-mediated signals and other cytokines

CLINICAL IMPORTANCE OF CLASS SWITCHING:

•In the absence of CD40 or CD40L, B-cells secrete only IgM and fail to switch to other isotypes

•X-linked hyper-IgM syndrome: inactivating mutations in the CD40L gene, located in the X chromosome

•much of the serum antibody is IgM

•defective heavy chain class switching

•Patients with defective CMI versus intracellular microbes

MECHANISM OF HEAVY CHAIN CLASS SWITCHING

WHAT YOU NEED TO KNOW:

IgM-producing B-cells, which have not undergone switching contain a rearranged VDJ gene adjacent to the first constant region cluster (Cu) in their

heavy chain locus

Splicing of VDJ RNA to Cu RNA = heavy chain mRNA

heavy chain mRNA = translated to u heavy chain

= combines with a light chain producing IgM

***IgM antibody (1st antibody produced)

a) constant region downstream of Cu: where stimulation of transcription via signals from CD40 and cytokine receptors occurs

b) switch region: conserved region within the constant region except for C-theta

SWITCH RECOMBINATION: 3’ of Cu recombines with 5’ of switch region = all intervening DNA is deleted

RESULT OF SWITH RECOMBINATION

B-cells begins to produce a new heavy chain class (depending on C region of the antibody)

- IgG, IgE

Same specificity as the original B-cell

CYTOKINES & HEAVY CHAIN CLASSES

• Cytokines produced by helper T-cells determine which heavy chain class is produced by influencing which heavy chain constant region gene participates in switch recombination (T-cells as master controllers of immune responses)

• e.g. OPSONIZING ANTIBODIES: effect of IFN-g on B-cells complement the actions of this cytokine on phagocytes

• their role: bind to phagocyte Fc receptors & promote phagocytosis

• stimulated by: IFN-g of TH1 cells

• e.g. IgE

• stimulated by IL-5, a TH2 cytokine

SITE OF IMMUNE RESPONSE & HEAVY CHAIN CLASSES

• nature of antibody class may also be influenced by site of immune response

• e.g. IgA: major isotype produced in mucosal lymphoid tissues

• RATIONALE: mucosal tissues contain large number of B-cells able to switch to IgA and helper T-cells whose cytokines stimylate switching to IgA

• NOTE: IgA is the principal antibody class that can be actively secreted through mucosal epithelia

AFFINITY MATURATION• process by which the affinity of antibodies

produced in response to a protein antigen increases with prolonged or repeated exposure to that antigen

• advantage: ability of antibodies to bind to a microbe or microbial antigen increases if the infection is persistent or recurrent

• occurs in the germinal centers of lymphoid follicles

• result of somatic hypermutation of Ig genes in dividing B-cells followed by the selection of high-affinity B-cells by antigen displayed by follicular dendritic cells (FDC)

STAGES OF TD ANTIGENS HUMORAL IMMUNE RESPONSE (note different anatomic compartments)

REGULATION: ANTIBODY FEEDBACK MECHANISM

SECRETED ANTIBODIES FORM IMMUNE COMPLEXES WITH RESIDUAL ANTIGEN AND SHUT-OFF B-CELL ACTIVATION BY ENGAGING AN INHIBITORY Fc RECEPTOR ON B-CELLS

EFFECTOR MECHANISMS OF HUMORAL IMMUNITY

SIGNIFICANCE OF HUMORAL IMMUNITY

• RECALL: mediated by antibodies and important for protection against extracellular microbes and their toxins = PREVENTION

• only antibodies can mediate this function

• by blocking the ability of microbes to bind to and infect host cells

• by binding to microbial toxins and prevent them from damaging host cells

• ADDITIONAL FUNCTIONS: eliminate microbes, toxins and infected cells from the body

• NOTE: even if they cannot KILL intracellular microbes, they can bind to these microbes even before they can enter the host cells and thus preventing infections

• ADDITIONAL FUNCTIONS: eliminate microbes, toxins and infected cells from the body

• NOTE: even if they cannot KILL intracellular microbes, they can bind to these microbes even before they can enter the host cells and thus preventing infections

• most VACCINES: STIMULATES ANTIBODY PRODUCTION

PROPERTIES OF ANTIBODIES THAT DETERMINE EFFECTOR FUNCTIONS

•antibodies may function distant from their sites of production (so that they perform their functions throughout the body)

•protective antibodies are produced during the first response and in larger amounts during subsequent responses

•antibodies use their antigen-binding region (Fab) to bind to and block the harmful effects of microbes and toxins while their Fc region is used to activate diverse mechanisms that elimante these antigens and toxins

•heavy chain class switching and affinity maturation enhance the protective functions of antibodies

IMPORTANT TO KNOW

•What are the mechanisms used by circulating antibodies to combat different types of infectious agents and their toxins?

•What is the role of complement system in defense against microbes?

•How do antibodies combat microbes that enter via the GIT and RT?

•How do antibodies protect the fetus and newborn from infections?

EFFECTOR FUNCTIONS OF ANTIBODIES

NEUTRALIZATION OF MICROBES & TOXINS BY ANTIBODIES

Antibodies bind to and block (NEUTRALIZE) the infectivity of microbes and the interactions of microbial toxins with host cells

Neutralization does not allow an infection to take hold

ANTIBODY-MEDIATED OPSONIZATION & PHAGOCYTOSIS

opsonization: antibodies coat microbes and promote their ingestion by phagocytes

opsonins: molecules that coat microbes

ANTIBODY-DEPENDENT CELLULAR CYTOTOXICITY (ADCC)

• natural killer cells (NK) and other leukocytes may bind to antibody-coated cells and destroy these cells

• important in helminth infections

• helminths are too large to be phagocytosed

• thick teguments resistant to substances released by phagocytes (neutrophils and macrophages

• IgE and eosinophil tandem

COMPLEMENT ACTIVATION

LATE STEPS IN COMPLEMENT ACTIVATION

FUNCTIONS OF COMPLEMENT

REGULATION OF COMPLEMENT ACTIVATION

• mammalian cells express regulatory proteins that inhibit complement activation, thus preventing complement-mediated damage of host cells (adaptation of mammals)

• a) decay accelerating factor (DAF); disrupts the binding of Factor B to C3b or the binding of C4b2a to C3b thus terminating compelemnt activation by both the alternative and the classical pathways

• b) membrane cofactor protein (MCP): serves as cofactor for the proteolysis of C3b into inactive fragments (mediated by Factor 1)

• c) Type 1 complement receptor: same functions as MCP

• d) C1 inhibitor (C1 INH): stops complement activation early (at stage of C1)

• ABSENCE OF REGULATION: hypersensitivities; immunodeficiencies, etcThursday, July 19, 2012

REGULATION OF COMPLEMENT ACTIVATION

REGULATORY PROTEINS

HYPERSENSITIVITY TYPE 1: Anaphylactic hypersensitivity

IgG antibodies against the Fc portions of IgE that binds to mast cells has been approved for treatment of certain allergies, as it can block mast cell sensitization

MUCOSAL IMMUNITY• immunity when IgA produced in mucosal lymphoid tissues are actively transported

across epithelia and binds to and neutralizes microbes that enter through mucosal organs

• IgA: 60-70% of 3g of antibody produced by a health adult in his intestines

• ORAL POLIO VACCINE

EVASION OF HUMORAL IMMUNITY

Biology 151 lecture 4 2012 2013 (part 2 hi)

secondary

humoral immunity

kill intracellular

infect host

humoral immunitythursday

host cells

primary amp

eliminate

Technology

Biology 151 lecture 4 2012 2013 (part 1- cmi)

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