This paper will review the immune disease of New Zealand Black (NZB) mice and their F1 hybrids produced by mating with New Zealand White mice (NZB/NZW). It will attempt to highlight important recent observations made in many laboratories around the world without exhaustively reviewing all papers written on the subject. Previous reviews have emphasized pathological changes and disease descriptions in New Zealand mice (Howie and Helyer, 1968; Helyer and Howie, 1963 a). The present effort will stress the immunological abnormalities of these mice. An attempt will be made to relate these immunological abnormalities with genetic and viral factors known to be important in their disease processes. The authors and their co-workers have studied approximately 20 000 NZB and NZB/NZW mice with regard to natural history, immunology, pathogenesis of disease and therapy. They will draw upon this experience when possible to fill in details not available in published reports.

The pathogenesis of autoimmunity in New Zealand black mice.

Biological systems can be analyzed in terms of effector mechanisms and factors responsible for their control. Autoimmunity can be viewed as a two-stage process in which a breakdown in immunologic regulation activates immunologic effector mechanisms which result in autoantibody formation and tissue destruction. Immune reactions are mediated by a variety of difierent efiector cells. These include B lymphocytes and their plasmacell progeny which express their activity through synthesis and secretion of antibody molecules, T lymphocytes which are active in cellular immunity and delayed hypersensitivity, and monocytes and related tissue macrophages. These effector cells are regulated by an intricate network of controlling mechanisms which includes the nature and intensity of the antigenic stimulus, immunoglobulin-receptor molecules on lymphocyte-surface membranes which have specificity for antigen, free antibody which can compete with these cell receptors for antigen, immune complexes which can bind to other cell-membrane receptors and alter cell function, and specialized regulatory (helper and suppressor) T cells. Autoimmunity, whether manifest by B lymphocytes producing autoantibodies or by T lymphocytes and macrophages infiltrating and destroying target organs, may arise not as a primary effector-cell abnormality, but rather as the consequence of disordered immunologic control. Autoimmunity and autoimmune diseases are frequently associated with genetic and viral factors that interact with the immune system and influence regulation. Immune-response (Ir) genes located within the major

Disordered Immunologic Regulation and Autoimmunity

The pathogenesis of autoimmunity in New Zealand mice

Disordered immunologic regulation and autoimmunity.

Systemic lupus is a multi-system, inflammatory disorder characterized by the production of autoantibodies of multiple specificities, especially antibodies reactive with nuclear ligands, including native DNA (Steinberg 1992, Steinberg et al. 1991, 1984. 1990, Andrews et al. 1978, Tan 1985, Harada et al. 1994, Smith & Steinberg 1983). One ofthe impediments to understanding human systemic lupus has been its marked heterogeneity (Steinberg et al. 1992, 1991). Indeed, a comparable heterogeneity is observed among the several strains of mice which spontaneously develop SLE-like syndromes. Taken together, they demonstrate the genetic and pathogenetic heterogeneity oflupus (Andrews et al. 1978, Steinberg et al. 1984, Theofilopoulos & Dixon 1980, Ebling & Hahn 1980). Autoantibody production in murine and human lupus has historically been attributed to (i) the selective stimulation of autoreactive B cells by self antigens (or antigens cross-reactive with self) (Hardin 1986) or (ii) a more generalized process of immune dysregulation leading to multi-clonal B-cell activation (Klinman & Steinberg 1987a, 1987b, Budman et al. 1977, Becker et al. 1981). Several years ago, we proposed a synthesis of these ideas; that polyclonal activation initiated autoantibody production but that this process was perpetuated by autoantigen-driven immune stimulation (Klinman et al. 1990). Herein we expand upon that concept. Indeed, our emphasis on B-cell hyperactivity early in disease (e.g. Klinman & Steinberg 1987a, 1987b) has been inappropriately viewed as demonstrating a lack of recognition of the contribution of T cells to specific autoantibody production late in disease as well as to non-specific activation of B cells through their production of cytokines (Steinberg et al. 1980, Cohen et al. 1982, Datta et al. 1987. Rajagopalan et al. 1992. Inghirami 1988, Laskin et al. 1986, Harada et al. 1994). We have clearly stated that this is not the case (Steinberg 1989, Klinman et al. 1990). Rather, we have attempted to divide early events

Inquiry into murine and human lupus

NZB/NZW (B/W) and C57BL/6 mice were made tolerant to sheep erythrocytes with cyclophosphamide. Thymus or bone marrow cells from tolerant or untreated donors were injected in various combinations into syngeneic irradiated recipients and assayed for plaque-forming cells. In C57BL/6 mice both marrow and thymus transfer tolerance; however, in B/W mice only the bone marrow did so. Unexpectedly, the B/W thymus from tolerant donors cooperated fully with B/W marrow cells from untreated donors. Thus the B/W thymus did not express the donor animal9s tolerance status.

Inability of the NZB-NZW F 1 thymus to transfer cyclophosphamide-induced tolerance to sheep erythrocytes.

The effects of polyinosinic polycytidylic acid (poly l poly C), a known adjuvant, were studied in New Zealand and C57B1/6 mice, using sheep erythrocytes (SRBC) as antigens. The control C57B1/6 mice showed a 3.1 to 6.7 fold increase in plaque forming cells (PFC) to SRBC when poly l poly C was given with the SRBC. The New Zealand mice (NZB/NZW F1 hybrids) showed very little increase in PFC with the poly l poly C. These studies suggest that the New Zealand mice are already maximally stimulated to respond to SRBC and that additional adjuvant cannot augment their response.

Adjuvant effects on poly I poly C in New Zealand mice.

The development of autoimmunity in New Zealand mice is related to genetic, immunologic, and viral factors. Evidence is presented to suggest that thymus-dependent immune functions may be depressed and bone marrow-dependent functions augmented in these mice. Antibodies to RNA and DNA appear spontaneously and can also be induced by treatment with rI·rC. Antibodies binding rI·rC-14C in human lupus sera, in NZB/NZW F1 (B/W) mice developing lupus, and in NZB, ALN, and ALN/NZB mice have greatest specificity for reovirus double-stranded RNA. Treatment of B/W mice with RNA and cyclophosphamide induces immunologic tolerance, and suppresses antibodies binding rI·rC-14C. During recovery, the specificity of the antibodies is unaltered. Induction of tolerance in this way prevents the accelerated formation of anti-RNA antibodies normally induced by MLV. This finding suggests that virus-accelerated and natural disease occur through a similar mechanism, and supports the hypothesis that viruses may act as antigenic stimuli for a genetically hyper-responsive antibody-producing system.

/pdf/immune-cell-cooperation-viruses-and-antibodies-to-nucleic-57kszf5gea.pdf

Immune cell cooperation, viruses, and antibodies to nucleic acids in new zealand mice.

IT has been generally thought that nucleic acids are unable to elicit an immune response without carrier protein and adjuvant1. We have recently succeeded in accelerating the spontaneous formation of antibodies to RNA and DNA in New Zealand mice with polyinosinic · polycytidylic acid (poly I·C) without carrier protein or additional adjuvant2. We have also made New Zealand mice immunologically tolerant to subsequent challenge with poly I·C in complete Freund's adjuvant by pretreatment with poly I·C followed by Cyclophosphamide3. These studies in mice that spontaneously develop antibodies to nucleic acids suggested that poly I·C was immunogenic but did not prove that nucleic acids could be recognized immunologically by normal mice. We now report the induction of immunological tolerance to poly I·C in normal strains of mice as a method of demonstrating immunological recognition of this nucleic acid.

/pdf/cyclophosphamide-tolerance-as-a-test-for-antigenicity-of-48qb4mknk4.pdf

Cyclophosphamide Tolerance as a Test for Antigenicity of Nucleic Acids

The development of autoimmunity in New Zealand mice is related to genetic, immunologic and viral factors. Evidence was presented to suggest that thymus-dependent immune functions may be depressed and bone marrow-dependent functions augmented in these mice. Antibodies to RNA and DNA appear spontaneously and can also be induced by treatment with polyinosinic·polycytidylic acid (rI·rC). Antibodies binding 14 C-rI·rC in human lupus sera and in New Zealand mice developing lupus have greatest specificity for reovirus double-stranded RNA. Treatment of New Zealand mice with RNA and cyclophosphamide induces immunologic tolerance and suppresses antibodies binding 14 C-rI·rC. Induction of tolerance in this way prevents the accelerated formation of anti-RNA antibodies normally induced by Moloney leukemia virus. This finding suggests that virus-accelerated and natural disease occur through a similar mechanism, and supports the hypothesis that common viruses may act as an antigenic stimuli for a genetically hyper-responsive antibody-producing system.

Immune Cell Function, Viruses and Autoimmunity in New Zealand Mice

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