Although antibody diversity arises mainly from apparently random combinatorial and somatic mutational mechanisms acting upon a limited number of germline antibody genes, the antibody repertoire develops in an ordered fashion during mammalian ontogeny. A series of early pre-B and B-lymphocyte cell lines were examined to determine whether an ordered rearrangement of gene families of the variable region of immunoglobulin heavy chains (VH) may be the basis for the programmed development of the antibody response. The results indicated that the VH repertoire of fetal B-lineage cells is largely restricted to the VH 7183 gene family and that subsequent recruitment of additional VH gene families occurs during neonatal development. These results have important implications in understanding the ontogeny of immune function.

Current theories propose that systemic lupus erythematosus develops when genetically predisposed individuals are exposed to certain environmental agents, although how these agents trigger lupus is uncertain. Some of these agents, such as procainamide, hydralazine, and UV light inhibit T cell DNA methylation, increase lymphocyte function-associated antigen 1 (LFA-1) (CD11a/CD18) expression, and induce autoreactivity in vitro, and adoptive transfer of T cells that are made autoreactive by this mechanism causes a lupuslike disease. The mechanism by which these cells cause autoimmunity is unknown. In this report, we present evidence that LFA-1 overexpression is sufficient to induce autoimmunity. , hydralazine, and UV light can trigger human lupus (1, 2). These agents also inhibit T cell DNA methylation, and polyclonal as well as cloned human and murine CD4 ϩ T cells become autoreactive after treatment with these and other DNA hypomethylating agents (3-7). Adoptive transfer of T cells made autoreactive by this mechanism causes a lupuslike disease in unirradiated syngeneic recipients (6, 7), suggesting a mechanism by which these agents might induce lupus. However, how these agents modify T cells to make them pathogenic is unknown. LFA-1 overexpression was induced on cloned murineThe autoreactivity correlates with lymphocyte functionassociated antigen 1 (LFA-1) (CD11a/CD18) overexpression, and concentrations of anti-CD11a insufficient to affect antigen reactivity will completely inhibit the autoreactive response (8). This suggests that LFA-1 overexpression contributes to the autoreactivity, and inhibiting function of the additional molecules reverses it (8). Cloned human T cells transfected with a CD18 cDNA also overexpress CD11a/CD18 and become autoreactive (5), further supporting the relationship between LFA-1 overexpression and T cell autoreactivity. These observations raise the possibility that LFA-1 overexpression might also contribute to the development of autoimmunity induced by hypomethylated T cells. However, inhibiting T cell DNA methylation probably affects expression of multiple genes, and the ability of the hypomethylated cells to induce autoimmunity may require altered expression of more than one gene. In this report, we examined the role of LFA-1 overexpression in autoimmunity by stably transfecting a cloned murine T cell line with a CD18 cDNA construct. We then asked if the transfected cells become autoreactive and induce a disease similar to that caused by treating the same cells with Pca, a DNA methylation inhibitor. MethodsMice and peritoneal macrophage (Mø) isolation. Young (6-8 wk of age) female AKR (H-2, and SJL (H-2 s ) mice were obtained from The Jackson Laboratories (Bar Harbor, ME) and maintained in a specific pathogen-free environment. Peritoneal Mø were obtained by i.p. thioglycollate (Becton Dickinson and Co., Cockeysville, MA) injection and harvested 3 d later as previously described (6, 7).T cell culture. D10.G4.1 cells (9), obtained from the American Type Culture Collection (Rock...

Groups of Aotus (owl) monkeys were immunized with either the Plasmodiumfalciparum merozoite surfacecoat precursor protein and its processing fragments or a complex of high molecular mass rhoptry proteins and challenged with a lethal infection of the homologous P. falciparum Uganda Palo Alto (FUP) strain. No patent parasitemia could be detected on thick blood films of monkeys immunized with the merozoite surface antigens; however, only one of three monkeys immunized with the rhoptry proteins was partially protected, while two required drug therapy. The experiment clearly demonstrates that the merozoite surface-coat precursor protein can completely protect Aetus monkeys against a lethal infection of the human malaria parasite.

We investigated the prevalence and magnitude of naturally acquired humoral immune response to the major merozoite surface protein (MSP-1) in a malaria-endemic population in Papua New Guinea. A prospective longitudinal study in 0.5-15-year-old children was conducted for one year to examine the relationship between acquired immune response to MSP-1 and subsequent susceptibility to clinical disease. The prevalence and concentration of antibodies to both N-(195A) and C-terminal (BVp42) regions of MSP-1 as well as to the parasite-derived MSP-1 increased with age, with the highest prevalence and concentration of antibodies being detected for the parasite-derived MSP-1 molecule and the C-terminal region of MSP-1. As malaria morbidity decreases with age, a significant negative correlation was observed between antibody levels to both 195A and BVp42 and the incidence rate of clinical malaria. When age and past exposure were corrected for, only antibody concentrations against BVp42 and to a lesser extent parasite-derived MSP-1 were significantly associated with protection from clinical malaria and severe parasitemia. The reduction in the incidence rate of clinical malaria observed in individuals with high antibody concentration to MSP-1 may be due to antibodies directed against epitopes within the C-terminal region of MSP-1.

Cell-mediated and humoral immune status of free-ranging green turtles (Chelonia mydas) in Hawaii (USA) with and without fibropapillomatosis (FP) were assessed. Tumored and non-tumored turtles from Kaneohe Bay (KB) on the island of Oahu and from FP-free areas on the west (Kona/Kohala) coast of the island of Hawaii were sampled from April 1998 through February 1999. Turtles on Oahu were grouped (0-3) for severity of tumors with 0 for absence of tumors, 1 for light, 2 for moderate, and 3 for most severe. Turtles were weighed, straight carapace length measured and the regression slope of weight to straight carapace length compared between groups (KB0, KB1, KB2, KB3, Kona). Blood was assayed for differential white blood cell count, hematocrit, in vitro peripheral blood mononuclear cell (PBMC) proliferation in the presence of concanavalin A (ConA) and phytohaemagglutinin (PHA), and protein electrophoresis. On Oahu, heterophil/lymphocyte ratio increased while eosinophil/monocyte ratio decreased with increasing tumors score. Peripheral blood mononuclear cell proliferation indices for ConA and PHA were significantly lower for turtles with tumor scores 2 and 3. Tumor score 3 turtles (KB3) had significantly lower hematocrit, total protein, alpha 1, alpha 2, and gamma globulins than the other four groups. No significant differences in immune status were seen between non-tumored (or KB1) turtles from Oahu and Hawaii. There was no significant difference between groups in regression slopes of body condition to carapace length. We conclude that turtles with severe FP are imunosuppressed. Furthermore, the lack of significant difference in immune status between non-tumored (and KB1) turtles from Oahu and Kona/Kohala indicates that immunosuppression may not be a prerequisite for development of FP.