Wire Loop Lesions Research Articles

The CCL2-CCR2 axis determines whether glomerular endocapillary hypercellularity or wire-loop lesions develop through glomerular macrophage and neutrophil infiltration in lupus nephritis.

The CCL2-CCR2 axis is involved in lupus nephritis, however the precise roles in the mechanisms by which different pathological lesions develop after glomerular immune complex deposition remain elusive. Previously, we demonstrated that genetic CCR2 inhibition induced a histological switch from glomerular endocapillary hypercellularity to wire-loop lesions in murine lupus nephritis. This study aimed to clarify the CCL2-CCR2 axis-mediated cellular mechanism in the formation of these different pathological lesions. We injected MRL/lpr mouse-derived monoclonal IgG3 antibody-producing hybridomas, 2B11.3 or B1, into wild-type (WT) mice to selectively induce glomerular endocapillary hypercellularity or wire-loop lesions. The expression of chemokine and chemokine receptors was analyzed using RT-quantitative PCR and/or immunofluorescence. We found 2B11.3 caused glomerular endocapillary hypercellularity in WT mice with glomerular infiltration of larger numbers of CCR2-expressing macrophages and neutrophils phagocyting immune complex, whereas B1 induced wire-loop lesions. In glomerular endocapillary hypercellularity, CCL2 was identified as the ligand involved in the CCR2-positive cell infiltration; it was expressed by glomerular endothelial cells and macrophages. Notably, 2B11.3-induced glomerular endocapillary hypercellularity converted to wire-loop lesions with reduced glomerular macrophage and neutrophil infiltration in CCL2-deficient (Ccl2-/-) mice similarly observed in Ccr2-/- mice. Moreover, this histological conversion was also observed when both glomerular macrophage and neutrophil infiltration were inhibited in anti-Ly6G antibody-treated Ccr5-/- mice but not when only glomerular macrophage infiltration was inhibited in Ccr5-/- mice or when only glomerular neutrophil infiltration was inhibited in anti-Ly6G antibody-treated WT mice. In contrast, B1 injection caused wire-loop lesions in Ccl2-/- and Ccr2-/- mice, as observed in WT mice. Moreover, 2B11.3 induced CCL2 from glomerular endothelial cells to a larger extent than B1 when injected into Ccr2-/- mice. In conclusion, the CCL2-CCR2 axis determines whether glomerular endocapillary hypercellularity or wire-loop lesions develop by regulating glomerular infiltration of phagocytic cells: macrophages and neutrophils. © 2024 The Pathological Society of Great Britain and Ireland.

OA21 Clinical outcomes and predictors of difficult-to-treat lupus nephritis: observations from a single center retrospective cohort

Abstract Background/Aims Lupus nephritis (LN) is a serious manifestation of systemic lupus erythematosus (SLE). About 14-33% of LN patients fail to respond to standard treatment. In this study we evaluated the treatment outcomes of LN patients who failed to respond to standard first-line immunosuppressives and attempted to define the clinical characteristics of ‘difficult-to-treat’ (DTT) LN. Methods Records of all SLE patients from the lupus clinic in our center who underwent renal biopsy were reviewed. Those with class III, IV, and V LN were included. Demographic, clinical, laboratory and histopathological features were recorded. Any patient with inadequate response to first-line induction which, according to the ACR, is disease worsening at three months or treatment failure by six months or who did not have partial or complete response as per EULAR/ERA-EDTA definition, were classified as DTT LN. Those who achieved complete response but developed flares within 24 months of therapy warranting second induction were also considered DTT. All of these patients received a second induction therapy. The outcome of interest was a composite outcome of worsening creatinine, end-stage renal disease (ESRD) or death. Secondary outcomes included response rates, time to achieve response, progression to ESRD, mortality, and adverse events. Results We identified 181 SLE patients (91.7% female) with biopsy-proven LN with complete records who had at least 2-year follow-up from 2004 to 2022. Their age (median, IQR) was 29 (24-32) years, median duration of disease 48 (24-84) months, median SLEDAI-2K was 12 (8-16). Among the initial kidney biopsies, 71 (39.2%) were class III, 74 (40.8%) class IV, 23 (12.7%) pure class V and 13 (7.1%) class III/IV + V. Fifty-seven of 181 (31.4%) were identified as DTT. Among these, 28/57 (49.1%) received second induction treatment, 22/57 (38.6%) received three induction, and 7/57 (12.3%) received >3 induction. Being of male sex, presence of constitutional symptoms, serositis, hypertension, leucopenia, active sediments in the initial urinalysis, anti-Ro-60, anti-U1RNP, any antiphospholipid antibodies (aPLs), low C3, wire loop lesions, interstitial inflammation, fibrinoid necrosis, cellular or fibrocellular crescents, and glomerulosclerosis were significantly associated with DTT LN (Table 1). On multivariate logistic regression, only the presence of aPLs and active urinary sediments remained as independent predictors of DTT LN(table 1). A Kaplan-Meier plot showed the cumulative incidence of the composite outcome to be significantly high in the DTT group. After follow up of 250 months, 24/57 (42.1%) DTT patients were in complete remission and 11/57 (19.3%) in partial remission, while 22/57 (38.6%) remained non-responsive to treatment. Conclusion The burden of DTT LN was 30% in our cohort, of whom 65% responded completely to second or third inductions, while a significant proportion failed to achieve remission even with repeat induction. Presence of active sediments at initial diagnosis and co-existence of aPLs were independent predictors of DTT LN. Disclosure J.B. K l: None. A. Jose: None. V. G: None. B. Mashetty: None. G. M s: None. M. Gorijavolu: None. C. Kavadichanda: None. A. Gopal: None. C. Mariaselvam: None. M.M. Thabah: None. V.S. Negi: None.

Spatially Anchored Molecular Neighborhoods in Lupus Nephritis


 
 
 Background: 
 Lupus nephritis (LN) affects 1 in 3 individuals with systemic lupus erythematosus. Suboptimal treatment precipitates irreversible kidney damage, leading to end stage renal disease. Kidney damage in lupus is characterized by immune cells injuring epithelial, endothelial, and stromal cells. We characterized molecular neighborhoods composed of immune cells interacting with resident cells of the kidney through spatial transcriptomics (ST). 
 Methods: 
 Visium ST experiments were conducted in 8 healthy controls (233 glomeruli) and 3 LN samples (48 glomeruli). Cell type labels from the Kidney Precision Medicine Project single cell RNA-seq atlas were transferred to deconvolute ST spots into specific cell types. Using histology and NPHS2 expression, glomeruli were selected as functional tissue units. Data were normalized, dimensionally reduced, and clustered with Seurat v4. Spatially anchored gene signatures of LN were identified. Glomeruli were re-clustered according to cell composition, to identify associated neighborhoods by fisher’s exact test. We characterized the cell composition, differentially expressed genes (DEGs), and pathways of relevant neighborhoods. 
 Results: 
 Between LN and control glomeruli, we identified HSPA8, PLEK, COL1A2 DEGs, associated with hypoxia, fibrosis, and immune response. We identified glomerular neighborhoods consistent with immune complex deposition, endothelial dysfunction (e.g. wire loop lesions), and mesangial cell expansion enriched in LN (p<0.05). Immune complex-mediated injury neighborhoods were characterized by interferon signaling, endothelial cell migration, and vascular genesis, consistent with DEGs BST2, CXCL12, and ENG. Endothelial dysfunction neighborhoods present cellular adhesion, immune cell signaling, and hypoxic pathways. DEGs included ITGB2, HLA-DPB1, and EGR1. Pathways enriched in mesangial expansion neighborhoods included matrix adhesion, podocyte development, and ERK1 and ERK2 cascade, aligned with ITGB3, NPHS1, and APOE DEGs. 
 Conclusion/ Clinical Impact and Implications: 
 Neighborhood characterization provides insight into cell-cell interactions that drive kidney disease progression. Future directions will change how kidney biopsy specimens drive treatment by delineating specific cell-cell interactions, linking molecular and histopathological signatures, and defining genes associated with therapeutic resistance. 
 
 

CCR2- and CCR5-mediated macrophage infiltration contributes to glomerular endocapillary hypercellularity in antibody-induced lupus nephritis.

LN comprises various glomerular lesions, including endocapillary hypercellularity with macrophage infiltration. In this study, we aimed to clarify the involvement of macrophage-tropic chemokine receptors in the pathogenesis of these glomerular lesions. MRL/lpr mouse-derived monoclonal IgG3 antibody-producing hybridomas, 2B11.3 and B1, were injected intraperitoneally into BALB/c mice [wild type (WT)] to induce endocapillary hypercellularity and wire-loop lesions, respectively. The expression of chemokine and chemokine receptors was analysed by quantitative real-time PCR and IF. The roles of chemokine receptors in these lesions were evaluated using chemokine receptor-deficient mice or a selective CCR5 antagonist, maraviroc. 2B11.3 caused glomerular endocapillary hypercellularity with a significant number of glomerular CD68-positive macrophages. Further, enhanced expression of CCL2, CCL3, CCR2, CCR5 and CX3CR1 was observed in the renal cortex, compared with B1 injection, which induced wire-loop lesions. In 2B11.3-induced glomerular lesions, CD68 -positive glomerular macrophages expressed CCL2, CCL3, CCR2, CCR5 and CX3CR1, while glomerular endothelial cells expressed CCL2, CCL3, CX3CL1 and CCR2. When 2B11.3 was injected, CCR2-/- and CCR5-/-, but not CX3CR1-/-, mice exhibited reduced endocapillary hypercellularity, attenuated glomerular macrophage infiltration and improved serum blood urea nitrogen levels. Only CCR2-/- mice developed wire-loop lesions. B1 injection caused wire-loop lesions in these chemokine receptor-deficient mice to a similar extent as WT. Maraviroc treatment reduced 2B11.3-induced endocapillary hypercellularity and improved serum blood urea nitrogen levels. CCR2 and CCR5 regulate glomerular macrophage infiltration and contribute to the development of glomerular endocapillary hypercellularity in LN. CCR5 inhibition can be a specific therapy for endocapillary hypercellularity without inducing wire-loop lesions.

Immunohistochemical detection of citrullinated histone H3-positive neutrophils is useful for identifying active glomerular and interstitial lesions in antineutrophil cytoplasmic antibody-associated vasculitis.

Activated neutrophils release neutrophil extracellular traps (NETs), resulting in a form of cell death called NETosis. NET formation is reportedly involved in the onset of systemic lupus erythematosus and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Citrullination of histones is a key step in NET formation, and the presence of citrullinated histones in neutrophils may be associated with disease induction and activity. The aim of this study was to investigate the relationship between infiltrating citrullinated histone H3 (H3Cit)-positive neutrophils and disease specificity and activity in various glomerulonephritides. We selected 32 kidney biopsies with glomerulonephritides, including AAV, lupus nephritis (LN), Henoch-Schönlein purpura nephritis (HSPN), and poststreptococcal acute glomerulonephritis (PSAGN). We examined the presence of H3Cit in infiltrating neutrophils and their association with necrotising, crescentic lesions and tubulointerstitial lesions. In PSAGN and HSPN, we found many myeloperoxidase (MPO)+ neutrophils in glomeruli; however, only a few were H3Cit+. In LN, MPO+ neutrophils mainly existed in the margins of glomerular tufts forming wire-loop lesions, and some of these were noted to be H3Cit+ neutrophils. In contrast, we found a significantly higher frequency of H3Cit+ neutrophils, despite the small number of MPO+ neutrophils, in microscopic polyangiitis in AAV. In particular, H3Cit+ neutrophils were prominent in necrotising lesions along the glomerular capillaries. Moreover, we also found H3Cit+ neutrophils in the interstitium, with marked peritubular capillaritis in AAV. H3Cit immunostaining is a useful tool for identifying activated neutrophils. The frequency of H3Cit+ neutrophils is not only a disease-specific marker but also a potential marker for disease activity in AAV.

Association of explanatory histological findings and urinary protein and serum creatinine levels at renal biopsy in lupus nephritis: a cross-sectional study

BackgroundThe aim of the present study was to evaluate the association between the histology of active and chronic lesions and urinary protein and serum creatinine (SCr) levels, as common clinical endpoints in clinical trials for lupus nephritis (LN).MethodsIn total, 119 patients diagnosed with LN class III, IV, and V, as defined by the International Society of Nephrology/Renal Pathology Society, between 1990 and 2015, were enrolled in the present study. Multiple regression analysis was performed to explore semi-quantitative histological variables associated with urinary protein and SCr levels.ResultsThe mean age of the enrolled patients was 45 years, and 79% were female. The mean SCr and mean urinary protein levels at the time of renal biopsy were 0.87 mg/dl and 3.00 g/gCr, respectively. Class IV (71%) was the most common type of LN followed by class III (17%), and class V (13%). Multicollinearity was confirmed between monocellular infiltration (variance inflation factor [VIF] = 10.22) and interstitial fibrosis (VIF = 10.29), and between karyorrhexis (VIF = 4.14) and fibrinoid necrosis (VIF = 4.29). Fibrinoid necrosis and monocellular infiltration were subsequently excluded, and multiple regression analysis revealed that only the urinary protein level was correlated with wire loop lesions (β-coefficient [β]: 1.09 and confidence interval [CI]: 0.35 to 1.83), and that the SCr level was correlated with glomerular sclerosis (β: 1.08 and CI: 0.43 to 1.74).ConclusionAs urinary protein and SCr levels were not quantitatively associated with active lesions, they may not accurately reflect the response to remission induction therapy in patients with LN.

Refractory Proteinuria in a Patient with Lupus Nephritis.

### Case Answer A 43-year-old woman with a 20-year history of SLE and a 13-year history of lupus nephritis was referred to our hospital for evaluation of worsening proteinuria. During the past 20 years, the patient had experienced multiple flares of SLE, including central nervous system lupus and biopsy-proven renal flares, and hence, had received several pulses of intravenous methylprednisolone and cyclophosphamide. Four years before presentation, kidney biopsy to investigate increased urinary protein excretion of 6 g/d demonstrated both active and chronic glomerular lesions of lupus nephritis, including mesangial proliferation; wire-loop lesions; and numerous deposits in the subendothelial, intramembranous, subepithelial, and mesangial areas. After another pulse therapy, mycophenolate mofetil 1000 mg was added to prednisolone 10–15 mg/d. Azathioprine therapy was attempted but discontinued due to pancytopenia. Tacrolimus was given for a short period but discontinued due to …

Lupus nephritis with massive subendothelial deposits in a patient with autoimmune hepatitis-related cirrhosis

A 72-year-old Japanese woman with a history of autoimmune hepatitis-associated liver cirrhosis and portosystemic shunt was admitted to our hospital for evaluation of renal dysfunction, nephrotic range proteinuria, a high titer of anti-double-stranded DNA antibody, and hypocomplementemia. Renal biopsy showed massive subendothelial deposits (wire loop lesions), and class IV-G (A/C) lupus nephritis was diagnosed. Immunosuppressants, such as steroids (including intravenous methylprednisolone pulse therapy) and mycophenolate mofetil, could not prevent renal dysfunction. It was assumed that circulating immune deposits produced in the gastrointestinal tract entered the systemic circulation from the portal vein via the portosystemic shunt without hepatic clearance, resulting in massive subendothelial and mesangial accumulation compared to lupus nephritis patients without a shunt and causing renal injury.

A Central Role for HLA-DR3 in Anti-Smith Antibody Responses and Glomerulonephritis in a Transgenic Mouse Model of Spontaneous Lupus.

MHC, especially HLA-DR3 and HLA-DR2, is one of the most important genetic susceptibility regions for systemic lupus erythematosus. Human studies to understand the role of specific HLA alleles in disease pathogenesis have been hampered by the presence of strong linkage disequilibrium in this region. To overcome this, we produced transgenic mice expressing HLA-DR3 (DRβ1*0301) and devoid of endogenous class II (both I-A and I-E genes, AE(0)) on a lupus-prone NZM2328 background (NZM2328.DR3(+)AE(0)). Both NZM2328 and NZM2328.DR3(+)AE(0) mice developed anti-dsDNA and glomerulonephritis, but anti-dsDNA titers were higher in the latter. Although kidney histological scores were similar in NZM2328 and NZM2328.DR3(+)AE(0) mice (7.2 ± 4.3 and 8.6 ± 5.7, respectively, p = 0.48), the onset of severe proteinuria occurred earlier in NZM2328.DR3(+)AE(0) mice compared with NZM2328 mice (median, 5 and 9 mo respectively, p < 0.001). Periarterial lymphoid aggregates, classic wire loop lesions, and occasional crescents were seen only in kidneys from NZM2328.DR3(+)AE(0) mice. Interestingly, NZM2328.DR3(+)AE(0) mice, but not NZM2328 mice, spontaneously developed anti-Smith (Sm) Abs. The anti-Sm Abs were seen in NZM2328.DR3(+)AE(0) mice that were completely devoid of endogenous class II (AE(-/) (-)) but not in mice homozygous (AE(+/+)) or heterozygous (AE(+/-)) for endogenous MHC class II. It appears that only HLA-DR3 molecules can preferentially select SmD-reactive CD4(+) T cells for generation of the spontaneous anti-Sm immune response. Thus, our mouse model unravels a critical role for HLA-DR3 in generating an autoimmune response to SmD and lupus nephritis in the NZM2328 background.

The clinico-pathological features of lupus nephritis and the significance of ISN/RPS-2003 Class IV lesions

Background: The ISN/RPS-2003 classification of lupus nephritis should emphasize clinically relevant lesions and encourage uniformity and reproducibility in histopathological reporting. Objective: To describe the clinico-pathological features of lupus nephritis and discuss the significance of the ISN/RPS-2003 class IV-G and IV-S lesions. Method: The histopathological features and corresponding clinical data of 75 patients with lupus nephritis were analysed using the International Society of Nephrology/Renal Pathology Society ISN/RPS - 2003 classification. This was a retrospective descriptive study carried out over a period of two and a half years at the Department of Pathology, Faculty of Medicine, Colombo. Results and conclusions: Lupus nephritis was commoner in females (88%, 66/75), with 52%, (36/75) in the 21-30 year age group. ANA positivity (93%, 70/75) was the commonest ACR (American College of Rheumatology - 1997) criterion to clinically diagnose SLE. Asymptomatic sub-nephrotic proteinuria was found in 47% (35/75), nephrotic syndrome in 21% (16/75) and hypertension in 17% ( 13/75). Endocapillary proliferation 84% (63/75) and wire-loop lesions 51% (38/75) were found to be the commonest histological features. 79% (59/75) had ISN/RPS class IV lupus nephritis (diffuse lupus nephritis) with the majority 93% (55/75) belonging to class IV-G (predominantly diffuse global lesions) and the remainder to class IV-S (predominantly segmental lesions). The pathogenesis of class IV-G lesions is thought to be immune complex mediated where as class 1V-S lesions are thought to show injury analogous to systemic vasculitides, unrelated to immunologic injury. Data on the prognostic outcomes of the two groups is conflicting because class IV-G is morphologically heterogenous, with two prognostically and pathogenetically distinct subcategories. Journal of Diagnostic Pathology 2014; 9(2): 14-22

Classification of lupus glomerulonephritis: an update

Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disease commonly affecting the kidneys, mostly mediated by immune complexes, resulting in a spectrum of glomerular lesions. They range from mesangial proliferative, focal proliferative (often segmental) with 50% of glomeruli affected, and membranous glomerulonephritis, depending on individual susceptibility, environmental triggers and the physic-chemical characteristics of the immune deposits. The clinical manifestations include varying degrees of proteinuria, hematuria, nephrotic syndrome, renal insufficiency and hypertension. The proliferative categories can be qualified by several additional features, such as the pattern of proliferative disease, crescents, wire loop lesions and hyaline thrombi, the latter two representing amount and location of immune deposits apparent by light microscopy. Classification of lupus nephritis has evolved from the first version in 1975 as the original WHO classification. Subsequent versions have incorporated additional prognostic features into the various classes/categories. The current ISN/RPS classification of lupus glomerulonephritis has gained wide acceptance and was published in 2004, following an international consensus with significant refinement of the definitions and classes. The advantages and problems associated with this classification are discussed, based on subsequent clinicopathologic validation studies in the last 10 years.

Protocol renal biopsy in patients with lupus nephritis: a single center experience.

Renal biopsy plays an indispensable role in the diagnosis and management of patients with lupus nephritis (LN). A number of studies have evaluated the role of a repeat biopsy in case of disease relapse or treatment unresponsiveness. We studied 40 patients with LN with renal biopsies performed at baseline and after six months of therapy. The baseline and protocol biopsies were compared with respect to histological class transformation, crescents, tubular atrophy, interstitial fibrosis and glomerulosclerosis. We also compared serum creatinine, hemoglobin, systemic lupus erythematosus disease activity index (SLEDAI) scores, 24-h urine protein excretion and C3levels as well as activity index (AI) and chronicity index (CI) at baseline and at six months. Comparison of means was made by paired t test, McNemar test and marginal homogeneity test (multinomial data). Histological class transformation was seen in 10 patients (25%). Intra-class progression to greater chronicity was seen in 10 other patients (25%).There was an increase in glomerulosclerosis, tubular atrophy, interstitial fibrosis and a reduction in cellularity, crescent formation and wire loop lesions in the protocol biopsy. A decline in AI (6.05 vs. 2.50, P <0.001) and SLEDAI scores (8.1 vs. 3.7, P <0.001) and an increase in CI (0.68 vs. 2.52, P <0.001) was observed at the time of protocol biopsy. Our study shows a trend toward greater chronicity in protocol biopsies in LN.

Fractalkine expression and CD16+monocyte accumulation in glomerular lesions: association with their severity and diversity in lupus models

Fractalkine (Fkn) is expressed on injured endothelial cells and is a membrane-bound chemokine that attracts cells expressing its receptor, CX3CR1, including CD16(+) monocytes (CD16(+) Mos). To clarify the role played by Fkn in the development of glomerular lesions in lupus nephritis, we examined Fkn expression and CD16(+) Mo accumulation induced in experimental C.B-17/Inc-scid/scid (SCID) lupus model mice by injection of IgG(3)-producing hybridoma clones obtained from MRL/lpr mice. Glomerular Fkn expression and accumulation of CD16(+) Mos were semiquantitatively evaluated using laser capture microdissection and real-time PCR. Injection of the 2B11.3 and 7B6.8 clones induced formation of glomerular proliferative and wire-loop lesions, respectively. Immunohistological analysis of the localization of Fkn and CD16(+) Mos revealed that Fkn expression and CD16(+) Mo accumulation were markedly elevated in glomerular lesions induced by 2B11.3, whereas no elevation was detected in those induced by 7B6.8. In addition, to examine the contribution of glomerular Fkn to the development of proliferative lesions, L cells producing an Fkn antagonist (Fkn-AT) were transplanted into SCID mice exhibiting proliferative lupus nephritis (DPLN) induced by 2B11.3. Notably, transplantation of the Fkn-AT-producing cells was functionally and histologically protective against this DPLN. Taken together, our findings suggest that Fkn and CD16(+) Mo accumulation are partially associated with the severity and diversity of histology of lupus nephritis.

Leukocytes and the kidney contribute to interstitial inflammation in lupus nephritis

Interstitial leucocyte infiltration, a prominent feature of lupus nephritis, predicts deterioration of renal function. We used two models of lupus nephritis in mice, one with chronic spontaneous disease and the other with acute interferon-alpha (IFN alpha)-mediated disease. The latter is characterized by the virtual absence of interstitial infiltration. In vivo migration assays showed that splenic leukocytes from spontaneously nephritic mice tended to migrate into non-inflamed syngeneic kidneys. This was enhanced if the recipient kidneys were already inflamed. Kidneys from both chronically and acutely nephritic mice showed similar ability to recruit splenic leukocytes from chronically diseased mice. Leukocytes from acutely diseased mice, however, failed to migrate into chronically inflamed kidney. Compared with those with chronic nephritis, the kidneys of acute nephritic mice expressed less of the inflammatory chemokine CXCL13/BLC. Moreover, leukocytes from acute nephritic mice displayed impaired migration, in vitro, to T-cell chemokine attractants. This study links leukocyte infiltration to both kidney chemokine expression, and leukocyte chemotaxis to kidney-expressed chemokines.

Kidney disease in systemic lupus erythematosus (SLE) of children--morphometric analysis of kidneys from autopsy cases.

We have investigated the histopathological changes of kidney from 16 autopsy cases of children with systemic lupus erythematosus (SLE) using morphometric and immunohistochemical methods. These 16 cases accounted for 61% of the child autopsy cases with SLE registered in the data base "Annual of the Pathological Autopsy Cases in Japan" during the nine years from 1984 to 1992. Based on the histologic and morphometric findings, we divided the SLE-associated renal disease into three types: glomerular (3 cases), vascular (3 cases) and non-renal (10 cases) types. The glomerular and vascular types had renal lesions, while in the non-renal the main changes were found in extrarenal tissues. Of the 16 cases examined, three showed diffuse proliferative glomerulonephritis, with one of the three having crescentic formations in the glomeruli. Two of the three had wire-loop lesions. Recently the crescentic or wire-loop lesions are rarely experienced even in renal biopsy and autopsy of adult cases. The vascular type was characterized by necrotizing angiitis (1 case) and severe intimal thickening of interlobular arteries (2 cases), but they had no advanced glomerular lesion. Morphometric methods allowed us to demonstrate that the severity of arterial lesions, especially intimal thickening, does not correlate with that of glomerular lesions in children.

Cloning and cDNA sequence analysis of nephritogenic monoclonal antibodies derived from an MRL/lpr lupus mouse

Production of IgG3 in MRL/Mp- lpr/lpr (MRL/lpr) lupus mice is one of the major factors to develop glomerulonephritis (GN) in these mice. To examine molecular characteristics of IgG3 responsible for GN in these mice, hybridoma clones producing IgG3 antibodies were prepared from one unmanipulated MRL/lpr mouse. Two clones, 2B11.3 and 7B6.8, were nephritogenic; that is, they caused severe glomerular lesions when injected to normal mice, moreover with a different histopathological manifestation. The 2B11.3 clone generated diffuse cell-proliferative lesions, while those induced by the 7B6.8 clone resembled wire loop lesions in human lupus nephritis. The cDNA sequence analysis of 7B6.8 antibody and the other IgG3 antibody, 1G3, non-nephritogenic, revealed that the C regions of the heavy and light kappa chains were completely the same between them. Furthermore, they were identical in deduced amino acid sequences to those from non-autoimmune BALB/c mice, indicating no allelic difference of Igh-8 between these two strains. The V regions of 2B11.3 and 7B6.8 antibodies were composed of different sets of V H, D, J H, V k and J k. Although both of the V H belonged to the J558 family, they seemed to use a different V H germline gene. These findings suggest that GN in MRL/lpr mice is generated by the expansion of clonally different B cells producing particular antibodies possibly with a different pathogenetic potency.

Non-H-2 genes alter the H-2 determined susceptibilities in immune complex nephritis

These experiments examined the effects of genes outside of the H-2 region on disease susceptibility and pathogenesis. Four strains of mice with the susceptible H-2 type, H-2d, but different non-H-2 genes were studied. B10, D2, Balb/c, NZB, and DBA/2J mice were injected with 4 mg of apoferritin i.p. q.d. for 28 days. B10, D2 and Balb/c mice developed proliferative and crescentic glomerulonephritis. NZB mice developed proliferative and crescentic glomerulonephritis with wire loop lesions suggestive of lupus. DBA/2J mice developed only minimal mesangial proliferation without crescents or necrosis. Electron microscopy showed subepithelial and mesangial deposits in B10, D2, moderate subepithelial and mesangial deposits in Balb/c, and marked mesangial, subendothelial and subepithelial deposits in NZB. Immunofluorescence demonstrated the presence of IgG, IgM, C3 and apoferritin in these deposits. The DBA/2J mice had only minimal mesangial deposits by immunofluorescence and electron microscopy. These experiments demonstrate that non-H-2 genes alter the H-2d determined disease susceptibility seen in H-2 congenic mice. NZB genes can alter the disease so that lupus-like lesions develop and DBA/2J genes can substantially ameliorate the disease.

Systemic lupus erythematosus with interstitial pneumonitis and systemic angiitis

A case of SLE with simultaneous occurrance of interstitial pneumonitis and systemic angiitis after administration of antibiotics and antituberculous drugs is reported.A 24-year-old woman developed fever and arthralgia during her first pregnancy. On admission in April 1980, she had a mild proteinuria, casturia, hypergammaglobulinemia, positive antinuclear antibodies, high titers of anti-DNA antibody and hypocomplementemia. Circulating immune complex was positive. Renal biopsy revealed mild mesangial proliferation and wire loop lesions in glomeruli. A diagnosis of SLE was made and prednisolone 40 mg daily was effective. In March 1982, fever relapsed when prednisolone was tapered to 10 mg daily. On the second admission, facial erythema was noted. Anti-DNA antibody was 304 U/ml (normal 10 U/ml), CH50 13.7 U/ml, CRP 2+ and the erythrocyte sedimentation rate 54 mm per hour. Prednisolone was increased to 30 ml daily. Fever subsided and titers of anti-DNA antibody decreased. In May 1982, fever, mononeuritis multiplex, dry cough and mild dyspnea developed when she was treated with Cefaclor for a carious tooth. In June, combination therapy with SM, INH and RFP was added because another SLE patient in the same ward was discovered to have pulmonary tuberculosis. Soon after psychosis, tremor and rigidity developed and dyspnea worsened. Blood gas analysis revealed severe hypoxemia and an X-ray film of the chest revealed diffuse interstitial infiltration in both lungs. Interstitial pneumonitis, CNS lupus and systemic angiitis were suspected. Pulse therapy with methylprednisolone was started with rapid improvement of hypoxemia and neurological symptoms. Interstitial pneumonitis relapsed again after slight reduction of prednisolone. The patient died after massive gastrointerstinal bleeding and anuria.At autopsy, subacute interstitial pneumonitis was observed in both lungs without evidence of cytomegalic inclusion body, Pneumocystis carinii or other opportunistic infections. Generalized angiitis in healing phase with adventitial fibrosis, intimal thickening, mural thrombosis, and ruptured internal elastic laminae was found in small arteries of kidneys, heart, liver, pancreas, spleen, small intestine, adrenal glands and ovaries. However, no evidence of angiitis was found in pulmonary arteries. Ruptured internal elastic laminae were found in the main coronary arteries.This case represents a rare combination of interstitial pneumonitis and systemic angiitis in SLE, in which antibiotics and antituberculous drugs were implicated as triggering factors.

A case of systemic lupus erythematosus-progressive systemic sclerosis overlap syndrome with a nephrotic syndrome

This patient was a 16-year-old girl who was diagnosed as a systemic lupus erythematosus (SLE)/progressive systemic sclerosis (PSS) overlap syndrome with 8 year history.She was in good health until 1970, when she noticed subcutaneous bleeding. The diagnosis of idiopathic thrombocytopenic purpura was made and she was treated with corticostreoids. In 1973, butterfly rash, polyarthritis, hemolytic anemia and LE cells phenomenon developed and she was diagnosed as SLE. In 1975, sclerodermatous skin changes with Raynaud's phenomenon developed. The area of sclerosis was rapidly spread from her fingers to the trunk and she was diagnosed as PSS besides SLE. In 1979, she admitted to Keio university hospital because proteiuria, which has appeared since 1977, developed to nephrotic syndrome. On the labolatory examinations, a skin biopsy showed an atrophy of the epidermis and a proliferation of collagen fibers in the dermis. The deposition of IgM at the dermal-epidermal junction was found. A renal biopsy demonstrated wire-loop lesions. In the serum from this patient, many autoantibodies, anti-RNP, anti-Sm, anti-Og (Scl70) and anti-ds DNA antibodies, were found. circulating immune complexes were also detected in the serum by Raji cell assay.In summary, this patient had a typical SLE/PSS overlap syndrome and had autoantibodies specific for both SLE and PSS. Circulating immune complexes and immune complex nephritis were present in this rare case.

Ultrastructural observations on the parotitis autoimmunica in the NZB/NZW hybrid mice.

The lesions of the spontaneously occurring sialoadenitis in the parotid gland of New Zealand Black/New Zealand White (NZB/NZW) hybrid mice were studied with the light microscope and the electron microscope. The inflammatory mononuclear cell infiltrates of the glands observed adjacent to glandular vessels and ducts were found to consist of several different cell types. Lymphoid cells (large, medium sized and small lymphocytes) were the most common, but plasma cells, histiocytes and macrophages were also encountered. Furthermore lymphoid cells were frequently observed inside the basement membrane of acini as well as INTERcalated ducts. Evidence of cell damage of the epithelium invaded by lymphoid elements included loss of cytoplasmic density, vesiculation of the endoplasmic reticulum, the appearance of cytoplasmic vacuoles, and cellular lysis. All the animals studied displayed moderate to advanced glomerular, wire-loop lesions in the kidneys. The light and electron microscopic findings indicate that the parotitis in NZB/NZW mice is basically a vasculitis. Duct cell proliferation and epimyo-epithelial island formation, which are common features in Sjögren's syndrome, are totally lacking in the material studied.