title: B cells expressing a natural polyreactive autoantibody have a distinct phenotype and are overrepresented in immunoglobulin heavy chain transgenic mice.
abstract: 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.
authors.affiliation: Department of Pathology L113, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Tian
authors.forename: Michael
authors.initials: M
authors.lastname: Beardall
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.forename: Ju
authors.initials: J
authors.lastname: Li
authors.forename: David C
authors.initials: DC
authors.lastname: Parker
authors.forename: Nina
authors.initials: N
authors.lastname: Casanova
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Bakke
authors.forename: Ching
authors.initials: C
authors.lastname: Chen
mesh_terms: 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
chemical_list: D001323:Autoantibodies; D007143:Immunoglobulin Heavy Chains