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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
Thursday, July 19, 2012
PHASES OF HUMORAL IMMUNE RESPONSES
Thursday, July 19, 2012
TD & TI ANTIGENS
Thursday, July 19, 2012
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
Thursday, July 19, 2012
PRIMARY & SECONDARY IMMUNE RESPONSE
Thursday, July 19, 2012
PRIMARY & SECONDARY IMMUNE RESPONSE
Thursday, July 19, 2012
So how do antigens stimulate B-lymphocytes?
Thursday, July 19, 2012
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
Thursday, July 19, 2012
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)
Thursday, July 19, 2012
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
Thursday, July 19, 2012
The Function of Helper T-lymphocytes in Humoral Immune Responses to Protein Antigens
Thursday, July 19, 2012
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
Thursday, July 19, 2012
INTERACTIONS OF T-CELLS & B-CELLS IN LYMPHOID TISSUES
Thursday, July 19, 2012
ANTIGEN PRESENTATION BY B-LYMPHOCYTES TO HELPER T-CELLS
B-cells act as APC
Thursday, July 19, 2012
HELPER T-CELL-MEDIATED ACTIVATION OF B-LYMPHOCYTES
Thursday, July 19, 2012
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
Thursday, July 19, 2012
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
Thursday, July 19, 2012
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)
Thursday, July 19, 2012
MECHANISM OF HEAVY CHAIN CLASS SWITCHING
WHAT YOU NEED TO KNOW:
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
Thursday, July 19, 2012
MECHANISM OF HEAVY CHAIN CLASS SWITCHING
WHAT YOU NEED TO KNOW:
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
Thursday, July 19, 2012
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
Thursday, July 19, 2012
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
Thursday, July 19, 2012
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)
Thursday, July 19, 2012
STAGES OF TD ANTIGENS HUMORAL IMMUNE RESPONSE (note different anatomic compartments)
Thursday, July 19, 2012
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
Thursday, July 19, 2012
EFFECTOR MECHANISMS OF HUMORAL IMMUNITY
Thursday, July 19, 2012
SIGNIFICANCE OF HUMORAL IMMUNITY
Thursday, July 19, 2012
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
Thursday, July 19, 2012
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
Thursday, July 19, 2012
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
• most VACCINES: STIMULATES ANTIBODY PRODUCTION
Thursday, July 19, 2012
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
Thursday, July 19, 2012
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?
Thursday, July 19, 2012
EFFECTOR FUNCTIONS OF ANTIBODIES
Thursday, July 19, 2012
EFFECTOR FUNCTIONS OF ANTIBODIES
Thursday, July 19, 2012
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
Thursday, July 19, 2012
ANTIBODY-MEDIATED OPSONIZATION & PHAGOCYTOSIS
opsonization: antibodies coat microbes and promote their ingestion by phagocytes
opsonins: molecules that coat microbes
Thursday, July 19, 2012
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
Thursday, July 19, 2012
COMPLEMENT ACTIVATION
Thursday, July 19, 2012
COMPLEMENT ACTIVATION
Thursday, July 19, 2012
LATE STEPS IN COMPLEMENT ACTIVATION
Thursday, July 19, 2012
FUNCTIONS OF COMPLEMENT
Thursday, July 19, 2012
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
Thursday, July 19, 2012
REGULATORY PROTEINS
Thursday, July 19, 2012
Thursday, July 19, 2012
Thursday, July 19, 2012
HYPERSENSITIVITY TYPE 1: Anaphylactic hypersensitivity
Thursday, July 19, 2012
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
Thursday, July 19, 2012
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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
Thursday, July 19, 2012
EVASION OF HUMORAL IMMUNITY
Thursday, July 19, 2012