8 th lecture

8th lecture

The collaborations between innate and adaptive immunity.

Antibody types and functions.

THE EFFECTS OF B CELLS ON THE INNATE ARM OF THE IMMUNE SYSTEM

(HUMMORAL IMMUNITY)

Antigen binding

Complement binding site

Placental transfer

Binding to Fc receptors

THE CONSTANT REGION OF AN ANTIBODY CAN BIND Fc RECEPTORS (FcR)

FcR activation occurs when the antibody forms a complex with an antigen

Sequence variability of H/L-chain constant regions

VARIABILITY IN THE CONSTANT REGION HEAVY AND LIGHT CHAINS DETERMINES THE

CLASS OF IMMUNOGLOBULIN

Sequence variability of H/L-chain constant regions

Isotype

• IgG - gamma (γ) heavy chains• IgM - mu (μ) heavy chains• IgA - alpha (α) heavy chains• IgD - delta (δ) heavy chains• IgE - epsilon (ε) heavy chains

HUMAN IMMUNOGLOBULIN CLASSES

Encoded by different structural gene segments (Isotypes)

• kappa (κ)• lambda (λ)

Heavy chain types:

Light chain types:

!

FcγR (gamma) can only bind IgG immunoglobulinsFcαR (alpha) can only bind IgA immunoglobulins

FcεR (epsilon) can only bind IgE immunoglobulins

!

Different cells express different Fc receptors on their surface

Expression of Fc receptors on the surface of cells is relatively constant (INFγ macrophages)

Fc receptors are activated not from a free antibody but by antibody-antigen complex

Antibodies of different isotypes activate different cells and have different effector functions

FcRAffinity for Immunoglobulin Cell Distribution Function

FcγRI (CD64) High (Kd < 10-9 M); binds

IgG1 and IgG3, can bind monomeric IgG

Macrophages, neutrophils; also eosinophils

Phagocytosis; activation of phagocytes

FcγRIIA (CD32) Low (Kd > 10-7 M) Macrophages, neutrophils; eosinophils, platelets

Phagocytosis; cell activation (inefficient)

FcγRIIB (CD32) Low (Kd > 10-7 M) B lymphocytes Feedback inhibition of B cells

FcγRIIC (CD32) Low (Kd > 10-7 M) Macrophages, neutrophils, NK cells

Phagocytosis, cell activation

FcγRIIIA (CD16) Low (Kd > 10-6 M) NK cells Antibody-dependent cell-mediated cytotoxicity

FcγRIIIB (CD16) Low (Kd > 10-6 M); GPI-

linked protein

Neutrophils Phagocytosis (inefficient)

FcεRI High (Kd > 10-10 M);

binds monomeric IgE

Mast cells, basophils, eosinophils

Cell activation (degranulation)

FcεRII (CD23) Low (Kd > 10-7 M) B lymphocytes, eosinophils, Langerhans cells

Unknown

FcαR (CD89) Low (Kd > 10-6 M) Neutrophils, eosinophils, monocytes

Cell activation?

ISOTYPE SWITCHING

Ig isotype Serum concentration

Characteristics, functions

12-14 mg/ml

Major isotype of secondary (memory) immune response

Complexed with antigen activates effector functions (Fc-receptor binding, complement activation

Trace

amounts

The first isotype in B-lymphocyte membrane

Function in serum is not known

Trace amounts

Major isotype in protection against parasites

Mediator of allergic reactions (binds to basophils and mast cells)

3-3,5 mg/ml

Major isotype of secretions (saliva, tear, milk)

Protection of mucosal surfaces

1-2 mg/ml

Major isotype of primary immune responses

Complexed with antigen activates complement

Agglutinates microbes The monomeric form is expressed in

B-lymphocyte membrane as antigen binding receptor

MAIN CHARACTERISTICS OF IMMUNOGLOBULIN ISOTYPES

B CELL ACTIVATION AND THE GERMINAL CENTER

Somatic mutationAffinity maturationIsotype switchingMemory

The progress of these germinal center reactions depend on T cell signals!

ISOTYPE SWITCHING IS T-DEPENDENT

B cell

Helper T cell

IL-2IL-4IL-5

IL-2IL-4IL-5 IgM

IgG

IgA

IgE

IL-2IL-4IL-6IFNγ

IL-5TGFβ

IL-4

B cell proliferation, differentiation and isotype switching

TRANSPORT PROCESSES INVOLVING THE Fc RECEPTORS

Neonatal Fcγ receptor for transport of maternal IgG across

the placenta

Poly Ig receptors for IgA transport across the epithelium to the

mucosal surface

Antigen binding

Complement binding site

Placental transfer

Binding to Fc receptors

FcγRn on the placenta facilitate the transfer of maternal IgG to the

fetus’s circulation, recognizing the constant region of IgGs

Pathological consequences of placental Pathological consequences of placental transport of IgGtransport of IgG

(hemolytic disease of the newborn)(hemolytic disease of the newborn)

Passive anti-D IgG

anti-RhIgM

EFFECTOR FUNCTIONS OF ANTIBODIES

Antibody-mediated immune responses

• Opsonization• Neutralization• Complement fixation• ADCC

ANTIBODY EFFECTOR FUNCTIONS

OPSONIZATION

ANTIBODY EFFECTOR FUNCTIONS

NEUTRALIZATION

ANTIBODY EFFECTOR FUNCTIONS

COMPLEMENT FIXATION

Binding of complement protein 1 to IgG or IgM immunoglobulins on a bacterial surface

ANTIBODY EFFECTOR FUNCTIONS

COMPLEMENT FIXATION

Complement 1 protein and the immunoglobulin bound to the bacteria cause the binding of more complement proteins

ANTIBODY EFFECTOR FUNCTIONS

COMPLEMENT FIXATION

More complement proteins are recruited leading to the death of the extracellular pathogen (bacteria) by forming pores in it

Antibodies target virus infected cells, flagging them for the recognition by natural killer (NK) cells

ANTIBODY EFFECTOR FUNCTIONS

ANTIBODY-DEPENDENT CELL CYTOTOXICITY

THE EFFECTS OF T CELLS ON THE INNATE ARM OF THE IMMUNE SYSTEM

MACROPHAGES

RECEPTORS AND CELL-SURFACE MOLECULES OF MACROPHAGES

TLR4 + CD14

MHCI

MHCII

TLR – pattern recognition Rs

CR1 (CD35)

CR3 (CD11b/CD18)

LFA1 (CD11a/CD18)

FcRIII (CD16)

FcRII (CD32)

FcRI (CD64)

Ag + IgG complex

Mannose receptor

Scavenger receptor

Mϕ

!!

EXTRACELLULAR PATHOGEN PHAGOCYTOSIS AND KILLING

KILLING THROUGH LYSOSOMAL ENZYMES, OXYGEN AND NITROGEN SPECIES

Activation of macrophages

IFN

IL-12IL-18

Th1 cell NK cell activation

Inflammatory cytokines Antimicrobial substances

Microorganism

TNF

IL-6 IL-12

Activation of macrophagesInflammatory cytokines

Leukocyte recruitment

THE LOCATION OF INNATE AND ADAPTIVE INTERACTIONS

KINETICS OF AN IMMUNE RESPONSE AGAINST PATHOGENS