8 th 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 immunoglobulins FcαR (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

FcR Affinity for ImmunoglobulinCell DistributionFunction FcγRI (CD64) High (K d < M); binds IgG1 and IgG3, can bind monomeric IgG Macrophages, neutrophils; also eosinophils Phagocytosis; activation of phagocytes FcγRIIA (CD32) Low (K d > M)Macrophages, neutrophils; eosinophils, platelets Phagocytosis; cell activation (inefficient) FcγRIIB (CD32) Low (K d > M)B lymphocytesFeedback inhibition of B cells FcγRIIC (CD32) Low (K d > M)Macrophages, neutrophils, NK cells Phagocytosis, cell activation FcγRIIIA (CD16) Low (K d > M)NK cellsAntibody-dependent cell-mediated cytotoxicity FcγRIIIB (CD16) Low (K d > M); GPI- linked protein NeutrophilsPhagocytosis (inefficient) FcεRI High (K d > M); binds monomeric IgE Mast cells, basophils, eosinophils Cell activation (degranulation) FcεRII (CD23) Low (K d > M)B lymphocytes, eosinophils, Langerhans cells Unknown FcαR (CD89) Low (K d > M)Neutrophils, eosinophils, monocytes Cell activation?

ISOTYPE SWITCHING

MAIN CHARACTERISTICS OF IMMUNOGLOBULIN ISOTYPES

B CELL ACTIVATION AND THE GERMINAL CENTER Somatic mutation Affinity maturation Isotype switching Memory The progress of these germinal center reactions depend on T cell signals!

ISOTYPE SWITCHING IS T-DEPENDENT B cell Helper T cell IL-2 IL-4 IL-5 IL-2 IL-4 IL-5 IgM IgG IgA IgE IL-2 IL-4 IL-6 IFNγ IL-5 TGFβ 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 transport of IgG (hemolytic disease of the newborn) Passive anti-D IgG anti-Rh IgM

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) Fc  RIII (CD16) Fc  RII (CD32) Fc  RI (CD64) Ag + IgG complex Mannose receptor Scavenger receptor MϕMϕ ! !

EXTRACELLULAR PATHOGEN PHAGOCYTOSIS AND KILLING

KILLING THROUGH LYSOSOMAL ENZYMES, OXYGEN AND NITROGEN SPECIES

Activation of macrophages

IFN  IL-12 IL-18 Th1 cell NK cell activation Inflammatory cytokines Antimicrobial substances Alternative activation: Mannose receptor – endocytosis Th2 chemokines NOS inhibition Tissue regeneration IL-4 IL-13 Th 2 cell Microorganism TNF IL-6IL-12 IL-10 T cell APC Inactivation Activation of macrophages Inflammatory cytokines Leukocyte recruitment

THE LOCATION OF INNATE AND ADAPTIVE INTERACTIONS

KINETICS OF AN IMMUNE RESPONSE AGAINST PATHOGENS