Induction of murine autoimmune disease by chronic polyclonal B cell activation.

In vivo, prolonged polyclonal activation of B cells by the nonantigenic but potent mitogenic lipid A portion of lipopolysaccharide (LPS-R595) resulted in acceleration of the late life systemic lupus erythematosus disease of female MRL/n, BXSB, and NZW mice, mimicking the time, form, and histopathological features characteristic of their early life disease counterparts, i.e., MRL/l females, BXSB males, and (NZB X NZW)F1 females. Similar polyclonal B cell activation of "immunologically normal" mice has less effect and led to a limited expression of autoimmune disease. This R595-induced autoimmunity and immune complex-mediated disease seemed to be the direct result of activation of the immune system and not from other effects of endotoxin since C3H/HeJ, a strain lacking lymphocyte receptors for LPS-R595, had neither serological nor histological evidence of autoimmune disease despite identical treatment.

BALB/cAn B cells and T cells have distinct susceptibilities to cytotoxic effects of snake venom.

Previous studies have analyzed abilities of snake venoms to preferentially kill certain animal cells. Some studies have examined selective cytotoxic effects of snake venoms on B and T lymphocytes, but few studies have determined abilities of snake venoms to interact with B and T cells at distinct stages of cellular development. Thus, this study has analyzed susceptibilities of immature and mature BALB/cAn splenic B cells and T cells to cytotoxic effects of crude venoms of snakes belonging to the families of Crotalidae, Elapidae, and Viperidae. Both mitogen-stimulated and unstimulated BALB/cAn Ig- splenic T cells are sensitive to cytotoxic effects of snake venoms whereas mitogen-stimulated but not unstimulated Ig+ splenic B lymphocytes are sensitive to snake venoms. We also find that BALB/cAn myelomas but not B cell lymphomas are sensitive to cytotoxic effects of snake venoms. In addition, plaque forming cells making IgG1 subclass in BALB/cAn mitogen-stimulated spleens and in myelomas are preferentially killed by venom of pit viper Bothrops asper. Thus, the cytotoxic effects of crude snake venoms can distinguish BALB/cAn PFC making IgG1 subclass from other B and T cells.

The preferential effects of chloroquine on the IgM and IgG subclass responses to TI and TD antigens in BALB/cAn mice.

This study has determined the effects of chloroquine on the IgM and the IgG subclass responses of BALB/cAn mice to both thymus-independent (TI) and thymus-dependent (TD) antigens, and has found that in antigen-unprimed BALB/cAn mice chloroquine adversely affects antibody responses to both TI and TD antigens. However, in antigen-primed mice the immune responses to TD antigens were unaffected by chloroquine. The IgGl subclass response, but not necessarily other IgG subclass or IgM responses to TI and TD antigens, was adversely affected by chloroquine in unprimed mice only. Thus, in unprimed, but not in antigen-primed, BALB/cAn mice, chloroquine preferentially decreased the IgGl subclass responses to both TI and TD antigens.

Strain-dependent IgG subclass response patterns.

Previous studies have shown that antigens preferentially stimulate IgG subclasses. However, the immunologic processes responsible for the patterns of IgG subclasses stimulated by antigens are probably complex and are certainly unclear. To define some of the genetic controls of IgG subclass expression in mice, we have studied the patterns of IgG subclasses elicited by antigens in BALB/cAn, C57BL/6N, derived recombinant inbred strains, and derived Ig congenic strains. This study shows that both thymus-independent antigens and thymus-dependent antigens stimulate different patterns of IgG subclasses in BALB/cAn and C57BL/6N. Furthermore, analysis using recombinant inbred strains and Ig congenic strains shows that the patterns of IgG subclasses stimulated by all antigens are linked to Ig allotype. In contrast, only the IgG subclass patterns stimulated by thymus-dependent antigens are linked to major histocompatibility complex haplotype. This study also shows that the Ig allotype-linked controls of IgG subclass response patterns are located telomeric to a BAB14 intra-heavy chain variable region recombinant site. Therefore, this region of mouse chromosome 12 may contribute to the control of IgG subclass selection in the B cell.

The cellular basis for resistance to induction of tolerance in BXSB SLE male mice.

The autoimmune BXSB male mouse early in life displays a resistance to tolerance induction that is common with the other autoimmune strains (MRL/1, NZB x W, and NZB) whereas its female counterpart, which in early life is immunologically normal, is easily tolerized. The cellular basis for the BXSB male's resistance to tolerance induction with DHGG was investigated by using adoptive male-female cell transfer systems. We found that irradiated female recipients of male T-depleted bone marrow cells, plus either male or female thymus cells, resisted tolerance induction, had hyperactive splenic Ig-secreting cells, and developed early glomerulonephritis. Recipients of male thymic cells plus T-depleted female bone marrow cells could be tolerized, did not have enhanced Ig secretion, and did not develop glomerulonephritis. Furthermore, donor male T-depleted bone marrow cells--but not male thymic, female thymic, or female bone marrow cells--resisted induction of tolerance before their transfer to produce lymphoid chimeras.

Autoimmune mice and stimulated normal mice make lambda 1 with increased V region diversity.

Previous studies of the genetic bases of murine SLE have defined gene segments that encode the H chain and the kappa L chain of anti-DNA, anti-Sm, and anti-IgG autoantibodies. As a result of these studies, the genetic origins of autoantibody H chains and kappa L chains are better understood, but little remains known about the genetic bases of autoantibody lambda-chains. Thus, we have analyzed serologically the germ-line and somatic origins of lambda 1 L chains in antibodies of normal mice and in both antibodies and autoantibodies of autoimmune mice. This study finds an increased lambda 1 diversity in both Ag-stimulated mice and autoimmune mice. This study also finds that the lambda 1 L chains in antibodies of unstimulated normal mice have the gene segment-encoded variable region, V lambda 1. In contrast, additional genetic processes appear to make the lambda 1 V regions of antibodies in Ag-stimulated normal mice and the lambda 1 V regions of both antibodies and autoantibodies in autoimmune mice. The increased lambda 1 diversity that we found in both Ag-stimulated mice and autoimmune mice might be caused by mutational processes creating antibody diversities. Therefore, the same somatic processes might be able to make both antibody and autoantibody lambda 1 diversities.

Isotypes of spontaneous and mitogen-induced autoantibodies in SLE-prone mice.

A common cellular abnormality of all murine strains prone to systemic lupus erythematosus (SLE) is an increased spontaneous polyclonal expansion of B cells. Our findings support the existence of this SLE-associated abnormality because the numbers of B lymphocytes secreting all the different IgG subclasses and IgM in spleens of all lupus-prone mice are elevated, compared to levels of normal splenic immunoglobulin-producing cells. We also report that 1) spontaneous polyclonal stimulation of immunoglobulin in autoimmune mice is preferential for subclass, and that the preferentially stimulated isotypes in each SLE strain consistently dominate both circulating and kidney-deposited immune complexes; 2) distinct patterns of isotype preference exist among the autoimmune strains determined by inherent B cell proliferative abnormalities or by B cell proliferation affected by thymus-derived lymphocytes; and 3) chronic administration of the TI B cell mitogen Lipid A in late-life SLE-prone mice induces an early-life glomerulonephritis with auto-antibodies of an isotype composition characteristic of those spontaneously produced by inherently abnormal B cells of early-life lupus mice.