Human immunoglobulin transgenes undergo rearrangement, somatic mutation and class switching in mice that lack endogenous IgM.
We have generated transgenic mice that contain human-sequence Ig miniloci and, because they are also homozygous for a targeted disruption of their endogenous heavy chain genes, must rely on the transgene sequences for B cell receptor expression. Although the human transgenes contain only a fraction of the intact human heavy chain locus, these defined sequences are able to at least partially restore the humoral immune system in the mouse. B cells expressing human heavy chains develop in the bone marrow, populate peripheral lymphoid tissue and respond specifically to antigen. Furthermore, the heavy chain transgenes contain both human mu and gamma 1 coding exons as well as the respective mu and gamma 1 switch regions. The sequences included within the transgene are sufficient to direct class switch recombination. Transgene sequences are also sufficient to direct somatic mutation of the class-switched heavy chain genes. These observations define the upper limit of the cis-acting sequences necessary to direct heavy chain class switching and somatic mutation.
GenPharm International, Mountain View, CA 94043.
L D
LD
Taylor
C E
CE
Carmack
D
D
Huszar
K M
KM
Higgins
R
R
Mashayekh
G
G
Sequar
S R
SR
Schramm
C C
CC
Kuo
S L
SL
O'Donnell
R M
RM
Kay
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D001483:Base Sequence; D015139:Blotting, Southern; D002454:Cell Differentiation; D005434:Flow Cytometry; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain / Q000502:physiology; D005803:Genes, Immunoglobulin; D006801:Humans; D007114:Immunization; D017578:Immunoglobulin Class Switching / Q000502:physiology; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D017710:Lymphocyte Transfusion; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation / Q000502:physiology; D014162:Transfection
D007143:Immunoglobulin Heavy Chains