Fc Receptors Oct. 28, 2009 Extra reading on web Daniel Conrad 423 MSB, I. CD23

CD23 – Member of the C-type animal lectin family

Trimeric structure means Avidity is important in Binding.

CD23 Summary Only Fc receptor that with no relationship to Ig superfamily Two isoforms exist – differ only in first six amino acids (in cytoplasm) Cleaved form loses trimeric structure – only interacts with IgE with low affinity Other ligands as well – CD21, CD11/CD18

CD23 Function Isotype control – IgE synthesis Antigen presentation – IgE complexes are internalized and degraded – peptides are then associated with class II MHC B cell growth and differentiation – in association with IL-1

Fc  RI

Initial model for the Fc  RI 1982

Current Model for the Fc  RI Shows interaction of  -chain with IgE

Fc  RI composition Three proteins required for expression in rodent – though  works in human alpha-chain binds IgE Beta – amplifies signal – binds src related kinase (lyn). Gamma – ITAMS are phosphorylated and interact with syk – this same gamma chain also is associated with Fc  RI, RIIIA

Depending on where it is expressed – can exist as  or as 

Cyrstal structure of complex has revealed site of interaction.

Fc  RI is part of a family of Multichain immune recognition Receptors (MIRRs) that use an ITAM activation scenario

ITAM Motif

ITAM (aggregation)

Receptor activates PTK either directly or indirectly – recruits syk family – activates PI3K which phos. PI3,4,5P3 – this recruits PLC  and Tec family – which produces IP3 – this releases intracellular Ca and opens CRAC (Ca release activated channels) (Cell 94:5-8, 1998 – reference for above figure if needed)

PH is Pleckstrin Homology domain – binds PI 3,4,5 P3

Fc  RI Mechanism ITAMs become phosphorylated (lyn) and bind syk, which then becomes activated Syk and Fyn activate– PI3 kinase – produces PtdIns-3,4,5 P 3 –Binds PLC  and Tec family member (btk) –IP3 is produced – causing release of intracellular calcium and influx of calcium (CRAC) Syk also activates vav – via SLP -- and eventual gene transcription

Summary of FcR structure showing ITAMs or ITIMs in cytoplasm

Cartoon showing glycerol-phosphotidyl inositol (GPI) linked protein PLD and PLC are enzymes that cleave at positions indicated

KAR is NK activating receptor

Examples of proteins that have an ITIM in cytoplasm

“ITIMs control ITAMs”

Mechanism of SHIP – cleaves 5’ phosphate from PI3,4,5-P3 – then IP3 cannot be made – blocking calcium release.

Fc receptor cluster in mouse and human

Evidence that another Fc Receptor was present FcRγ KO was more severe than FcγRI or FcγRIII α-chain. This was especially true if antibody class was IgG2a/IgG2b and the effector cell was myeloid in nature. Fcrl3 – 60% Id with FcγRIII α-chain. Charged aa in transmembrane domain

FcγRIV Expressed in mouse – binds IgG2a/2b best Expressed on macrophages and dendritic cells Opsonic Fc receptor – especially for these subclasses of IgG

IgA Transport