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Journal of Transmitted Diseases and Immunity
ISSN: 2573-0320
Volume 4
May 10-11, 2018
Frankfurt, Germany
Immunology Research 2018
Tissue Science 2018
Page 43
JOINT EVENT
2 2
n d
E d i t i o n o f I n t e r n a t i o n a l C o n f e r e n c e o n
Immunology and
Evolution of Infectious Diseases
&
1 2
t h
E d i t i o n o f I n t e r n a t i o n a l C o n f e r e n c e o n
Tissue Engineering and
Regenerative Medicine
B
-lymphocytes can modify their immunoglobulin (Ig) genes
to generate antibodies with a new isotype and enhanced
affinity. Activation-induced cytidine deaminase (AID) is the key
mutagenic enzyme that initiates these processes. How somatic
hypermutation (SH) and class switch recombination (CSR) are
targeted and regulated to understand how we achieve good
antibodies. The
trans-acting
factors mediating specific targeting
of AID and thereby SH and CSR have remained elusive. How
AID is recruited was still a big mystery. We show that mutant
E2A transcription factor with defect inhibition by the Ca
2+
sensor
protein calmodulin results in reduced B cell receptor (BCR),
IL4- plus CD40 ligand-stimulated CSR to IgE. AID is shown to be
together with the transcription factors E2A, PAX5 and IRF4 in a
complex on key sequences of the
Igh
locus in activated mouse
splenic B cells. Calmodulin shows proximity with them after
BCR stimulation. Direct protein-protein interactions are shown to
enable formation of the complex. BCR signaling reduces binding
of the proteins to some of the target sites on the
Igh
locus, and
calmodulin resistance of E2A blocks this reduction. Thus, E2A,
AID, PAX5 and IRF4 are components of a CSR and SH complex
that calmodulin binding redistributes on the
Igh
locus. We present
also that initiation of antibody diversification leads to formation of
amutasome, a complex betweenmany proteins that enable repair
at high error rate of the uracils made by AID on Ig genes but not
on most other genes. We show also that BCR activation, which
signals end of successful SH, reduces interactions between some
proteins in the complex and increases other interactions in the
complex with varying kinetics. Furthermore, we show increased
localization of SH and CSR coupled proteins on switch regions of
the
Igh
locus upon SH/CSR and that BCR signaling differentially
change the localization.
Biography
Thomas Grundström has completed his Doctorate at Umeå University in
1981 and his Medical degree in 1982. He was a Postdoc during 1982-1984
in the laboratory of Professor Pierre Chambon, Institut de Chimie Biologique,
Strasbourg, France, where he characterized the first discovered enhancer
of transcription. He is a Professor at the Department of Molecular Biology
at Umeå University since 1994. He has been studying Ca
2+
sensor proteins
and eukaryotic transcription and discovered the first direct Ca
2+
/calmodulin
inhibition of a transcription factor. He has characterized the Ca
2+
regulation of
many transcription factors and other regulatory proteins with a main focus
on the immune system. He is presently studying regulation of production of
antibodies. He studies how somatic hypermutation (SH) and class switch re-
combination (CSR) are targeted and the regulation of the protein complex that
performs SH and CSR.
Thomas.Grundstrom@umu.seRegulation of diversification and affinity
maturation of antibodies
Thomas Grundstrom
Umeå University, Sweden
Thomas Grundstrom, J Transm Dis Immun 2018, Volume 2
DOI: 10.21767/2573-0320-C2-004