Natural autoantibodies to thymocytes: origin, VH genes, fine specificities, and the role of Thy-1 glycoprotein.

Abstract

Summary15 SM/J mouse hybridoma antibodies that show antithymocyte autoantibody (ATA) activity by immunofluorescence staining were studied. Half of these antibodies react with determinants whose expression is associated with Thy-1, as shown by blocking experiments with antiThy-1 and loss of reactivity with Thy-1 -mutant cell lines . The Thy-1 dependence of three of these ATA is further confirmed by their reexpression on a Thy-1 gene transfectant . However, the remaining antibodies exhibited binding that showed little or no dependence on Thy-1. Furthermore, we find that most ATA derives from the Ly-1 B subpopulation, as demonstrated by lipopolisaccharideinduced ATA secretion in vitro and by comparison of ATA hybridoma frequencies. V region gene sequence data of 14 monoclonal ATA from Ly-1 B cell-derived hybridomas reveal the utilization of nine V genes belonging to four different V H families (J558, 3609, Q52, and Vgam3.8) . While we find that two of these hybridomas arose from a clonal expansion, we also find four examples of a 3609 family V gene utilized in clonally independent lines showing similar specificity. Yet another example of identical V gene usage by clonally unrelated cells is found in two J558 ATA of a distinct fine specificity. These data suggest that the enrichment of ATA B cells in the Ly-1 B subset is primarily due to repeated independent recruitment of B cells by antigen resulting in the expression of a restricted set of VH genes.

Analysis of the Individual Contributions of Igα (CD79a)- and Igβ (CD79b)-Mediated Tonic Signaling for Bone Marrow B Cell Development and Peripheral B Cell Maturation

“…Accordingly, MZ and B1 cells are present in a semiactivated state in which they are constitutively secreting Ab. Phosphocholine and phosphatidyl choline molecules are present in surface of different strains of Streptococcus, and natural Abs against these molecules may help to prevent infection by these pathogens (91)(92)(93)(94)(95)(96)(97). Taken together, these and our data support a model where generation of the different mature B cell populations depends on a different mechanism of BCR signaling.…”

Class switching and consecutive loss of dsDNA‐reactive B1a B cells from the peritoneal cavity during murine lupus development

“…The enrichment of autoreactive specificities in the B1a B cell compartment [8][9][10][11][12], their low activation threshold and the increased numbers of B1 B cells in various murine lupus models [4,6] have led to the speculation of involvement of these cells in the pathogenesis of autoimmunity. This assumption is supported by studies showing amelioration of murine lupus when B1 B cells were either genetically or physically depleted [16,17].…”

“…Besides the PC they can be detected in the spleens, blood and inflamed target organs [7]. Human and murine B1a B cells are enriched for autoreactive specificities targeting DNA, thymocytes, immunoglobulins and phosphatidylserine [8][9][10][11][12]. B1 cells have additionally been shown to be the source of anti-erythrocyte antibodies in a transgenic model of autoimmune hemolytic anemia [13].…”

Major histocompatibility complex class II expression distinguishes two distinct B cell developmental pathways during ontogeny.

“…It is known that the fetal repertoire contains a high frequency of B cells that are low affinity, polyreactive, and that often recognize self-antigens (37,38). It is interesting to note that the period during which the developing fetal/neonatal IgM + B cells lack class II antigens corresponds exactly to the period when newly generated B ceils are exquisitely sensitive to tolerance induction (39,40).…”