B cells expressing a natural polyreactive autoantibody have a distinct phenotype and are overrepresented in immunoglobulin heavy chain transgenic mice.
Despite stringent regulation of disease-associated autoantibodies, a substantial proportion of circulating Abs in sera of healthy individuals exhibit self-reactivity. These Abs are referred to as naturally occurring or natural autoantibodies (NAAs). To understand the origin and function of NAAs, we have generated a new site-directed transgenic mouse model in which a prerearranged VDJ gene coding for the H chain of a typical polyreactive NAA, ppc1-5, is inserted into the IgH locus. This H chain, when combined with its original L chain, the lambda1 L chain, yields a NAA that characteristically binds a variety of self and non-self Ags including ssDNA, actin, ubiquitin, and nitrophenyl phosphocholine. Despite their autoreactivity, B cells expressing ppc1-5H/lambda1 NAA are not negatively selected, but rather are overrepresented in the transgenic mice. The shift toward lambda1 expression mainly occurs during the transition of immature to mature B cells in the spleen, suggesting a BCR selection process. The ppc1-5H/lambda1 B cells exhibit a phenotype that is different from those of the known mature B cell populations, and they are located predominantly in the lymphoid follicles of the spleen and the lymph nodes. These B cells are functionally active, producing high levels of Abs in vivo and responding well to BCR stimulation in vitro. The findings indicate that the ppc1-5/lambda1 natural autoantibodies originate from a distinct B cell subset that may be positively selected by virtue of its poly/autoreactivity.
Tian
Qi
Q
Department of Pathology L113, Oregon Health and Science University, Portland, OR 97239, USA.
Beardall
Michael
M
Xu
Yang
Y
Li
Ju
J
Parker
David C
DC
Casanova
Nina
N
Bakke
Anthony C
AC
Chen
Ching
C
D000818:Animals; D000831:Animals, Newborn; D001323:Autoantibodies / Q000096:biosynthesis* / Q000235:genetics; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018390:Gene Targeting; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis / Q000235:genetics*; D016130:Immunophenotyping; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D016254:Mutagenesis, Insertional; D010641:Phenotype
D001323:Autoantibodies; D007143:Immunoglobulin Heavy Chains