Autoimmune Disease in NZB/Bl Mice

Abstract

During the last year we have studied autoimmune manifestations and pathological changes in mice of the inbred strain NZB/B1, confirming and extending observations of others at the University of Otago Medical School, Dunedin, New Zealand, (1,7,8,(18)(19)(20)(21), where the strain was developed b y Dr. Marianne Bielschowsky, and at the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia (2, 9, 24--26, 32, 42). The present report deals mainly with the pathology and the pathogenesis of glomerulonephritis in NZB/B1 mice, a model system of membranous glomerulonephritis with spontaneous and insidious onset, progressing through chronic stages, and almost certainly induced b y immunological, and autoimmune, mechanisms. Methods and MaterialsAnimals.--Dr. Marianne Bielschowsky kindly sent us a breeding nucleus of 4 males and 9 females from the sixtieth generation of her inbred strain of NZB/B1 mice. A colony of many hundred has been derived from this stock by brother-sister matings in first and second litters, now in the sixty-third generation. The diet has consisted of purina laboratory chow supplemented with lettuce and carrots and free access to water. Nursing does also received bread soaked in cows' milk, with 2 drops of cod liver oil added. A silica gel insecticide (permadust, Laboratory Essentials, Inc., West Islip, New York) was dusted on the wood-shaving beddings of mice over 3 weeks of age. Daily inspections, biweekly or monthly weighings, and laboratory observations were made, and are continuing to be made, on non-breeding males and females of this colony beginning at about 2 to 3 months of age and on retired breeders from 4 to 12 months of age. A few retired NZB

Immunopathology of NZB/Bl Mice

“…The degree of lymphoid hyperplasia and the number of plasma cells, including periodic acidSchiff positive Russell-body types, in spleen, lymph nodes, and thymus of tumor-bearing mice appeared to exceed even that which commonly occurs in NZB/B1 mice of comparable age (4 to 7 months) as they, and similarly the tumor-bearing mice, undergo antiglobulin (Coombs') test conversion and develop other manifestations of autoimmune hemolytic anemia. Surprisingly, the glomerular lesions of focal membranous glomerulonephritis (6,8) developed in a 2 month-old NZB/B1 mouse which had carried a tumor transplant for 4 wk and, in addition, diffuse membranous glomerulonephritis occurred in a tumor-bearing mouse when only 4 months of age. The structural manifestation of membranous glomerulonephritis in older N Z B / B I mice bearing transplanted tumors was in general severe and similar to that occurring in N Z B / B I mice of comparable age but not bearing tumor grafts (6,8).…”

“…Surprisingly, the glomerular lesions of focal membranous glomerulonephritis (6,8) developed in a 2 month-old NZB/B1 mouse which had carried a tumor transplant for 4 wk and, in addition, diffuse membranous glomerulonephritis occurred in a tumor-bearing mouse when only 4 months of age. The structural manifestation of membranous glomerulonephritis in older N Z B / B I mice bearing transplanted tumors was in general severe and similar to that occurring in N Z B / B I mice of comparable age but not bearing tumor grafts (6,8).…”

“…Studies are in progress to determine whether the filtrable agent has oncogenic properties and to investigate its role in the hemolytic disease (1-3) which characterizes NZB/B1 mice. Circulating and in vivo-localized antibodies with specificity for the structurally altered glomeruli in "spontaneous" renal disease of NZB/B1 mice have already been described (6), and, conceivably, these immunoglobulins may prove to be at least in part antiviral antibodies. A recent paper has described the occurrence of glomerulonephritis in AKR mice with leukemia produced by the inoculation of Friend or Rauscher virus (22).…”

Wild-Type Gross Leukemia Virus and the Pathogenesis of the Glomerulonephritis of New Zealand Mice

“…Mice.--The following mice were used: NZB mice from our colony (10); NZB, NZW, and (NZB o ~ )< NZW 9 ) F 1 hybrid mice produced from a breeding nucleus of NZB and NZW mice obtained from the Texas Inbred Mice Co., Houston, Tex., through the courtesy of Mr. Samuel M. Poiley, National Cancer Institute, National Institutes of Health, Bethesda, Md. ; C57BL/6 and AKR mice from our colony and from Jackson Memorial Laboratory, Bar Harbor, Maine; and CFW mice from Carworth Farms, New City, N. Y.…”

“…The cumulative mortality of NZB mice, mainly attributable to renal glomerular disease, increases in phase wittl the production of free G antibody (9). Murine leukemia virus (MuLV)-specified antigens and host immunoglobulins, presumably antibodies, are localized in vivo in the glomerular lesions (9,10). These findings implicate Gross leukemia virus in the etiology of glomerulonephritis of NZB mice and suggest that the host immune response to antigens of the G system (7,15,16), and hypersensitivity mediated by the deposition of G soluble antigen-antibody complexes in the glomeruli, are important contributory factors in the pathogenesis of the renal disease (9).…”