Autoimmune Renal Disease Research Articles

Influence of diet on vascular lesions in autoimmune-prone B/W mice.

Autoimmune-prone B/W mice, which are known to develop severe glomerulonephritis and vasculitis, also are found to develop arteritis and proliferative and fatty-proliferative lesions of the aorta and its branches as well as renal inflammatory lesions. High intake of saturated fat in the diet enhances the development of these atherosclerotic and autoimmune lesions significantly in female mice, whereas restriction of dietary calories and fat inhibits their development. Ad lib feeding of laboratory chow, high in fiber and low in fat, does not foster development of vascular lesions but does permit the development of autoimmune renal disease.

Spontaneous and induced autoantibodies to renal and nonrenal basement membranes in mice

(NZB × NZW)F 1 hybrid mice ( B W ) with lupus nephritis have, in rare instances, linear deposits of IgG on the renal tubular basement membrane (TBM). We have established that at least in one such unusual case this deposit is anti-TBM autoantibody. These spontaneously formed autoantibodies reacted with iso-, allo-, and xenogeneic TBM, but they were organ specific. Antibasement membrane autoantibodies were induced experimentally with xenogeneic TBM. Male B W , NZB, and random-bred mice immunized with rabbit TBM developed autoantibodies which reacted in vitro with TBM, glomerular basement membrane, lung basement membranes, and the basement membranes of seminiferous tubules. By contrast, in vivo deposition of IgG was seen in kidneys and testes but not in lungs. Despite the early presence of circulating autoantibodies (Day 8), renal tubulointerstitial lesions were not seen until Days 42 to 59 in 40 of 65 mice. The histopathologic involvement ranged from focal mononuclear cell infiltrates in the interstitium to severe disruption of tubules and TBM. Multinucleated giant cells were seen occasionally. IgG deposits were a mixture of complement- and noncomplement-fixing subclasses, but C3 was not readily detectable on GBM or TBM. C5+ and C5− strains developed similar renal lesions. By analogy with other models of autoimmune renal tubulointerstitial diseases, the lesions in mice may be caused by anti-TBM autoantibodies, but other undetermined pathogenetic mechanisms may also play a role.

Studies on the Pathogenesis of Experimental Autoimmune Renal Tubulointerstitial Disease in Guinea Pigs

It has been reported that strain 2 guinea pigs do not develop experimental autoimmune renal tubulointerstitial disease (RTD) by active or passive immunization. Under our experimental conditions strain 2 guinea pigs are susceptible to the induction of RTD. Typical moderate to severe renal lesions were seen 22 days after immunization with rabbit tubular basement membrane in complete Freund's adjuvant. Most Albany strain guinea pigs had severe RTD. Susceptibility to induction of RTD by passive transfer of antitubular basement membrane autoantibodies was studied in Albany (A) and strain 2 (2) guinea pigs, as well as in A leads to A, A leads to 2, and 2 leads to A radiation chimeras. Only some strain 2 guinea pigs had mild to severe renal lesions by day 9, but by day 19 all had typical histologic renal abnormalities. Albany guinea pigs already had moderate to severe RTD by days 9-10. Strain 2 differed from Albany recipients by a noticeable delay in the onset of lesions. Bone marrow transplants between Albany and strain 2 did not affect these susceptibility differences. A leads to 2 recipients responded like strain 2, and 2 leads to A like Albany. This indicates that the delay of onset of RTD in strain 2 is not a defect in the bone marrow-derived inflammatory cells.

Studies on the pathogenesis of experimental autoimmune renal tubulointerstitial disease in guinea pigs: 5. Deposition of C3PA on the tubular basement membranes

Studies on the nature of the mononuclear cell infiltrate and the humoral mediators of inflammation in experimental autoimmune renal tubulointerstitial disease (RTD) in guinea pigs have shown that: (i) Disease is induced by autoantibodies to tubular basement membrane (TBM); (ii) IgG and C3 are present along the TBM of diseased kidneys; (iii) RTD can be induced in guinea pigs with a total genetic C4 deficiency, but not in passive transfer recipients treated with cobra venom factor; and (iv) the initial accumulation of mononuclear cells can be inhibited by total-body irradiation. The present immunofluorescence studies indicate that the alternate (properdin) pathway of complement activation is involved, as was previously suggested by experiments in C4-deficient guinea pigs. We have identified C3PA (factor B) along the TBM of kidneys with RTD. In contrast, C4, an early component of the classic (hemolytic) complement sequence, was not seen.

Studies on the pathogenesis of experimental autoimmune renal tubulointerstitial disease in guinea pigs: II. Passive transfer of renal lesions by anti-tubular basement membrane autoantibody and nonimmune bone marrow cells to leukocyte-depleted recipients

Renal tubulointerstitial disease (RTD) in guinea pigs is induced by anti-tubular basement membrane (TBM) antibodies, complement, and radiosensitive mononuclear cells. The present experiments show that the bone marrow is the source of the initial cellular infiltrate. Groups of normal and irradiated guinea pigs were passively immunized to TBM; in addition, some of the leukocyte-depleted passive transfer recipients were injected with bone marrow cells from unimmunized donors. By day 6–8 RTD had occurred in 36 of 36 unmanipulated recipients, in none of 45 depleted animals, and in 18 of 25 given a combination of marrow cells and antibody. Under similar conditions, irradiated marrow cells or viable cells from thymus, spleen or lymph node did not elicit the accumulation of mononuclear cells in the renal cortex. Hence, mononuclear cells derived from the bone marrow play a major role in the pathogenesis.

Immunopathogenesis of Autoimmune Tubulointerstitial Nephritis

Abstract Autoimmune tubulointerstitial nephritis (TN) was induced in strain XIII and Hartley but not strain II guinea pigs after immunization with rabbit tubular basement membranes (TBM) in CFA. Strain XIII guinea pigs developed extensive autoimmune TN associated with high anti-TBM (aTBM) antibody titers and linear deposits of IgG along renal cortical TBM after immunization with 10 µg to 10 mg of TBM. In addition, autoimmune TN was passively transferred to strain XIII animals by the i.p. injection of aTBM sera obtained from actively immunized Hartley guinea pigs. In contrast, strain II guinea pigs did not develop autoimmune TN after active immunization (10 µg to 10 mg) with rabbit TBM in CFA, and only produced high aTBM antibody titers with the highest immunizing antigen dose. At this dose (10 mg) the strain II animals demonstrated linear deposits of IgG along renal cortical TBM but did not develop autoimmune TN. Further, recipient strain II guinea pigs did not develop autoimmune TN after passive transfer of aTBM antisera despite renal cortical tubular deposition of aTBM antibodies. Both inbred guinea pig strains produced antibodies reactive with rabbit and rat renal basement membranes. No evidence for differences in nephritogenic TBM antigens could be demonstrated between strain XIII and strain II TBM. These observations indicate that 1) genetic factor(s) influence the production of antibodies reactive to autologous TBM, 2) after the deposition of antibodies on the TBM, additional or related genetic factor(s) determine the full expression of this autoimmune renal disease, and 3) aTBM antibody deposition on renal TBM is not sufficient to elicit autoimmune TN.

Studies on the pathogenesis of experimental autoimmune renal tubulointerstitial disease in guinea pigs: 1. Inhibition of tissue injury in leukocyte-depleted passive transfer recipients

Renal tubulointerstitial disease (RTD) in guinea pigs is passively transferred to unmanipulated recipients by autoantibody to renal tubular basement membrane. The present experiments show that such tissue injury could not be induced in recipients depleted of radiosensitive circulating leukocytes before or 1 day after injection of antibody. Radioresistant phagocytic mononuclear cells, characteristic of RTD lesions, did not accumulate in the target organ in the absence of radiosensitive cells. When lethally irradiated recipients were reconstituted by bone marrow grafts and then given antibody, they developed RTD indistinguishable from that seen in unirradiated passive transfer recipients. There observations indicate that the initial accumulation of radiosensitive leukocytes in the target tissue is mediated by autoantibody and complement, and that progression of tissue damage depends to some extent on radioresistant mononuclear cells. Direct injury of renal tubules by complement and autoantibody was not observed.

Inhibition of experimental autoimmune renal tubulointerstitial disease in guinea pigs by depletion of complement with cobra venom factor

Passive transfer experiments have shown that autoimmune renal tubulointerstitial disease (RTD) in guinea pigs is caused by autoantibodies specific for tubular basement membrane (TBM). Further studies on the pathogenesis of this renal disease have implicated complement (C) as a possible mediator of antibody-dependent tissue injury because C3 is present along with IgG on the TBM. However, as shown in experiments with C4 deficient guinea pigs, no essential pathogenetic role could be ascribed to C4, suggesting the involvement of alternate pathway of complement activation. To delineate the role of C in this model, attempts were made to induce RTD by passive transfer in guinea pigs depleted of 95% of C with cobra venom factor (CoF). RTD could not be induced by anti-TBM antibodies alone. IgG and C3 must both be bound to TBM for a sufficient period of time before tissue injury can occur. An essential role for C participation in the pathogenesis of this model of autoimmune tubular nephritis is evident. Mononuclear cells, prominent in these lesions, appear to accumulate and proliferate in the renal cortex only when sufficient amounts of C are available. CoF did not seem to have a direct inhibitory effect on mononucular cells in this model.

Transmission of autoimmune disease by thymus transplantation in mice

A previous study demonstrated the development of autoimmune disease in CBA/H-T 6 T 6 (CBA-T 6 ) mice following neonatal thymectomy and replacement grafting from newborn NZB X NZW F 1 hybrid mice, animals which spontaneously develop autoimmune renal disease. The grafted mice developed glomerular disease with additional immunopathological markers such as positive antiglobulin, LE cell and latex nucleoprotein tests. These animals died prematurely in renal failure with uraemia. To extend these findings, a series of similarly thymectomized and grafted mice was studied in an elective killing programme, the criterion for inclusion being apparent good health. The present report concerns the results of immunofluorescent testing for antinuclear antibody (ANA) in 101 male and 92 female mice. The overall prevalence of ANA was 51% in the male and relatively constant throughout life. In the female, the prevalence was 59% with maxima at 3 and 7 mth. The incidence of ANA in ungrafted CBA-T 6 mice was close to zero. Additional findings included an increased prevalence of positive antiglobulin tests and of nucleoprotein antibody. Body weight and blood urea did not differ from controls, as expected in such an elective killing programme. However, histological study showed early glomerular changes. These results support the view that autoimmune disease has been transmitted by thymus transplantation from an autoimmune to a normal inbred strain of mice.

Experimental Autoimmune Renal Cortical Tubulointerstitial Disease in Guinea Pigs Lacking the Fourth Component of Complement (C4)

Abstract C4d guinea pigs develop experimental autoimmune renal tubulointerstitial disease indistinguishable from the disease observed in guinea pigs with circulating C4. These data demonstrate that an antibody-mediated autoimmune renal disease can occur in the absence of C4. We conclude: 1) complement may, at least in part, play a role in the pathogenesis, 2) complement activation does not occur via the classical sequence in this model, and 3) that activation and tissue injury may be mediated by an alternate complement pathway.

A rapid method for the separation of guinea pig IgGl and IgG2.

Immunoelectrophoretically pure IgG1 and IgG2 were isolated from sera of guinea pigs with experimental autoimmune renal tubular disease by chromatography on QAE-Sephadex A-50 (Pharmacia Fine Chemicals, Piscataway, N.J. using a two-step elution. As judged by indirect immunofluorescence tests of the fractions, 70% of the original autoantibody activity to tubular basement membrane was recovered.

Transfer of experimental autoimmune renal cortical tubular and interstitial disease in guinea pigs by serum.

Guinea pigs injected with rabbit tubular basement membranes and Freund's adjuvant develop progressive renal cortical tubulointerstitial disease and deposit autoantibodies in their cortical tubular basement membranes. The identical, even fatal, disease may be produced in normal guinea pigs by a single intraperitoneal injection of serums obtained from guinea pigs with this tubulointerstitial disease, provided such serums contain sufficient amounts of autoantibodies against tubular basement membranes.

Influence of natural and synthetic estrogens on the course of autoimmune disease in the NZB-NZW mouse.

AbstractAntinuclear antibodies were found in 64% of serum samples obtained from male NZB/NZW mice after 6 weeks of treatment with mestranol. Both female and male mice responded to this synthetic female hormone with marked elevations of serum α2‐ and β‐globulins; γ‐globulins were not increased. There was no evidence that mestranol accelerated the development of autoimmune renal disease in these animals. Treatment of hybrid New Zealand mice with mestranol, 17‐β‐estradiol and oophorectomy exerts divergent effects on serum proteins and the development of serologic abnormalities.

Malaria infection in adult NZB mice and in adult (NZB x NZW) F 1 hybrid mice.

Adult NZB mice were found to be more susceptible to infection with P. berghei than young mice of the same strain. This enhanced susceptibility was probably related to the presence of reticulocytosis in adult Coombs positive NZB mice and to the defective powers of cell mediated immunity occurring in adult mice of this strain. Over a short period of observation P. berghei infection did not have any effect on an established positive Coombs test. Infection of B/W mice with P. berghei at the age of 5–6 months had some protective effect on the development of their spontaneous autoimmune renal disease but this effect was less marked than when infection was induced at the age of 1 month.

Clinical Immunology and Allergy

ABSTRACT In the first half of the 20th century, the clinical practice of allergy was principally empiric, and treatment in major part consisted of desensitization techniques. The immunological knowledge is now being widely applied to such diverse fields as organ transplantation, the pathogenesis and treatment of malignant disease, and a variety of autoimmune disorders, renal disease, and infections. The clinical allergist sometimes found himself considerably deficient in the new immunology.Clinical Immunology and Allergy, edited by Leo H. Criep, appears aimed initially at the clinical allergist and represents an admirable attempt both to bring together much of the recent information on the immunology of the traditional atopic diseases and, at the same time, to embrace the wider applications of the immunology. The first part includes a well-organized section on fundamentals of immunology. This section is followed by the core of the book, Reactions of Hypersensitivity, which covers fairly comprehensively

AUTOIMMUNE RENAL DISEASE. THE PRODUCTION OF AUTOIMMUNE RENAL DISEASE IN THE RAT BY HOMOIMMUNIZATION WITH ORGAN-HETEROLOGOUS MATERIAL.

AUTOIMMUNE RENAL DISEASE. THE PRODUCTION OF AUTOIMMUNE RENAL DISEASE IN THE RAT BY HOMOIMMUNIZATION WITH ORGAN-HETEROLOGOUS MATERIAL.

Transfer of experimental auto-immune nephrosis in rats.

Summary1. Fourteen pairs of parabiosed litter mates were used. In 9 of these autoimmune nephrosis was produced in one of the paired rats by repeated i.p. injection of rat kidney suspensions incorporated in Freund's complete adjuvants. Nephrotic renal disease was noted in all 9 non-injected parabionts, simultaneously with or shortly after onset of proteinuria in the injected rat. In the 5 parabiosed pairs in which the injected rat failed to develop renal disease, the parabiont that had not been treated did not develop nephrotic renal injury. 2. The same antigenic material was given 3–9 times at 2-week intervals by i.v. injection to 12 rats. Slight and inconsistent proteinuria was noted in 5 and histological alterations of glomerular structures were observed in 2. A nephrotic syndrome of comparable severity was not noted in any of these animals. 3. Suspensions of lymphocytes obtained from the spleens of rats with incipient autoimmune renal disease were given by i.v. injection to 9 litter mates in which immu...