Vascular Immune Deposits Research Articles

UNUSUAL PRESENTATION OF LUPUS NEPHRITIS IN A 22 YEAR OLD MALE : A CASE REPORT

Systemic lupus erythematosus (SLE) is an autoimmune disease in which organ and cell undergo damage initially mediated by tissue binding autoantibodies & immune complexes.In most patients, autoantibodies are present for a few years before the rst clinical symptoms appears. It is ve to six times more prevalent in women than in men .Nephritis is usually the most serious manifestation of SLE, particularly because nephritis and infection are the leading cause of mortality in the rst decade of disease. We present a case of a 22 yr old male who came with complaint of bilateral pedal oedema and pufness of face since 1 month . On examination, patient was stable hemodynamically with pulse of 88 per minute, blood pressure of 110/80 millimeter of mercury with room air saturation of 99 percent and jugular venous pressure of 6-7 millimeters of water. He also had pallor in lower palpebral conjunctiva and bilateral pitting pedal oedema.There was no clubbing, icterus,cyanosis or lymphadenopathy. His routine blood investigations showed anaemia , leucocytosis , elevated creatinine, hyperkalaemia , hypoalbuminemia, iron deciency ,urine routine microscopy suggestive of RBC cast 60-70/high power eld . Complement C3 and C4 were low, ANA positive grade 3(1:1000) homogeneous and cytoplasmic speckled, ANA BLOT positive for dsDNA, nucleosome, Histones, Sm/RNP,Mi2b.His ultrasound (USG) revealed bilateral bulky kidney and heterogeneous with raised cortical echogenicity and normal size. His renal biopsy was done which showed diffuse lupus nephritis(ISN/RPS2018 modication)class IV and indices(modied NIH) of activity 15/24 and chronicity 2/12, necrotizing vascular lesions along with evidence of vascular immune deposits in diffuse immunoorescence studies and associated inammatory cells are noted. Patient received intravenous pulse therapy of methyl prednisolone 1gram for 5 days with monitoring of kidney function test. Patient was put on cyclophosphamide with hemodialysis for immunosuppression because patient was not responding to steroids, as seen by rising serum creatinine and urea levels and declining urine output. The patient improved dramatically, urine output increased and serum creatinine and urea decreased, therefore haemodialysis was discontinued, and the patient was managed conservatively and discharged on oral prednisolone with a monthly cyclophospmide injection.

Autoimmune markers and vascular immune deposits in Finkelstein-Seidlmayer vasculitis: Systematic literature review

Finkelstein-Seidlmayer vasculitis, also called acute hemorrhagic edema of young children or infantile immunoglobulin A vasculitis, is habitually a benign skin-limited small vessel leukocytoclastic vasculitis that mainly affects infants 24 months or less of age. Since this disease is commonly triggered by an infection, an immune-mediated origin has been postulated. To better appreciate the possible underlying immune mechanism of this vasculitis, we addressed circulating autoimmune markers and vascular immune deposits in patients contained in the Acute Hemorrhagic Edema BIbliographic Database, which incorporates all original reports on Finkelstein-Seidlmayer vasculitis. A test for at least one circulating autoimmune marker or a vascular immune deposit was performed in 243 cases. Subunits of complement system C4 resulted pathologically reduced in 4.7% and C3 in 1.4%, rheumatoid factor was detected in 6.1%, and antinuclear antibodies in 1.9% of cases. Antineutrophil cytoplasmic antibodies were never demonstrated. Immunofluorescence studies were performed on 125 skin biopsy specimens and resulted positive for complement subunits in 46%, fibrinogen in 45%, immunoglobulin A in 25%, immunoglobulin M in 24%, immunoglobulin G in 13%, and immunoglobulin E in 4.2% of cases. Infants testing positive for vascular immunoglobulin A deposits did not present a higher prevalence of systemic involvement or recurrences, nor a longer disease duration. In conclusion, we detected a very low prevalence of circulating autoimmune marker positivity in Finkelstein-Seidlmayer patients. Available immunofluorescence data support the notion that immune factors play a relevant role in this vasculitis. Furthermore, vascular immunoglobulin A deposits seem not to play a crucial role in this disease.

Revisiting vasculopathy in lupus nephritis: A renal biopsy evaluation study

Introduction:The classification of lupus nephritis (LN) on biopsy is essentially focused on morphologic changes in glomeruli. Renal vascular lesions are not addressed in detail in current classifications and are often overlooked. We aimed to determine the prevalence of vascular lesions in LN on biopsies and to compare these with biopsies not showing the vasculopathies.Methods:A total of 740 renal biopsies of LN were analysedfor presence of vasculopathies from January 2013 to June 2019. Of these, 527 (71.2%) biopsies showed vascular lesions (vascular group), which were further categorized into known five subtypes according to morphology and immunofluorescence (IF) findings. Remaining 213 (28.8%) biopsies constituted non-vascular group. Clinical, demographic and laboratory parameters were compared between these two groups.Results:The mean age was 27.95 ± 9.8 years and 27.0 ± 9.4 years in the vascular and non-vascular groups respectively with higher M:F (1:2 > 1:7) in vascular group. Majority of vasculopathies (257, 48.7%) were found in biopsies with class IV LN. Haematuria (69.8% vs. 20.1%), proteinuria (100% vs. 62%), anemia (48.3% vs. 3.60%) and hypertension (39.8% vs. 8.46%) were common in group I. Uncomplicated vascular immune deposits (426; 80.8%) were the most common vasculopathy and true vasculitis (4;0.8%) was least common. Activity and chronicity indices (7.35 ± 3 and 2.45 ± 1.5, respectively) were significantly higher in the vascular group. Activity index was highest in uncomplicated vascular immune deposits (7.45 ± 2.8) and chronicity index was highest in non-specific sclerotic vascular lesions (2.7 ± 1.6).Conclusion:Vascular involvement is common in LN. Uncomplicated vascular immune deposits were common vasculopathies whereas true vasculitis was least common. The morphology and IF both need to be carefully screened for the diagnosis of vasculopathies.

Immune deposits in skin vessels of patients with acute hemorrhagic edema of young children: A systematic literature review.

Acute hemorrhagic edema of young children is a benign skin-limited vasculitis mainly affecting children 2 to 24months of age, which is often considered the infantile variant of immunoglobulin A vasculitis (Henoch-Schönlein purpura).In most cases, the diagnosis is made on a clinical basis without a skin biopsy. A systematic review of the literature was performed to examine the reported prevalence of vascular immune deposits in skin biopsies of patients with acute hemorrhagic edema of young children. Testing for vascular immune deposits was performed in 75 cases (64 boys and 11 girls aged from 3.5 to 72, median 11months) published between 1970 and 2018. Vessel wall deposition of complement C3 was seen in 40 cases. Immunoglobulin M (N=24), immunoglobulin A (N=21), immunoglobulin G (N=13), and immunoglobulin E (N=3) were less frequently detected. Gender, age, clinical features, and disease duration were not statistically different in cases with and without vessel wall deposition of immunoglobulin A. Immune deposits in skin vessels, most frequently complement C3, are common in subjects with acute hemorrhagic edema of young children, providing furhter evidence that acute hemorrhagic edema, immunoglobulin A vasculitis, and pauci-immune vasculitides are different entities.

Renal Interstitial Arteriosclerotic Lesions in Lupus Nephritis Patients: A Cohort Study from China.

ObjectiveThe aim of this study was to evaluate renal arteriosclerotic lesions in patients with lupus nephritis and investigate their associations with clinical and pathological characteristics, especially cardio-vascular features.DesignA retrospective cohort study.ParticipantsSeventy-nine patients with renal biopsy-proven lupus nephritis, diagnosed between January 2000 and June 2008 from Peking University First Hospital.ResultsIn clinico-pathological data, patients with arteriosclerosis had higher ratio of hypertension and more severe renal injury indices compared with patients with no renal vascular lesions. More importantly, patients with renal arteriosclerosis had worse cardiac structure and function under transthoracic echocardiographic examination. Patients with renal arteriosclerosis tend to have higher ratios of combined endpoints compared with those of no renal vascular lesions, although the difference didn’t reach statistical meanings (P = 0.104).ConclusionRenal arteriosclerotic lesion was common and associated with vascular immune complex deposits in lupus nephritis. It might have a certain degree of association with poor outcomes and cardiovascular events, which needs further explorations.

Hypocomplementemic urticarial vasculitis syndrome – a case report

Hypocomplementemic urticarial vasculitis syndrome (HUVS) is a rare immune-complex small vessel systemic vasculitis involving kidney in about 50% of patients. Characteristic clinical features are recurrent urticaria, decreased serum complement, skin vasculitis, arthritis, eye inflammation, abdominal pain, glomerulonephritis and positive anti-C1q antibodies. We report a 36-year-old woman with a 12-year history of recurrent urticaria and 2 years of urticarial vasculitis. On admission, she also had arthritis, pleuritis and pericarditis, abdominal pain, pathologic urinalysis, low serum values of C3, C4 and CH50. All immunoserology was negative except for ANA 1:80 and anti-C1q 620 IU. ’Full-house’ immune complex vasculitis was demonstrated in skin and lung biopsies. A kidney biopsy showed diffuse proliferative segmental active and sclerosing glomerulonephritis with mesangial and endocapillary proliferation, neutrophil exudation, necrosis, extracapillary crescents and segmental and global glomerulosclerosis. ’Full-house’ glomerular and extensive extraglomerular vascular and tubulointerstitial immune deposits with dominant IgG, C3 and C1q were noted by immunofluorescence. Electron microscopy revealed electron dense deposits with an ultrastructural ’fingerprint’ pattern in the glomerular mesangium, transmembranous in capillary walls and in the arteriolar wall. Our patient fulfilled the criteria for HUVS and SLE, in accordance with the not infrequent clinical and immunoserological overlapping of the two diseases.

Inclusion of renal vascular lesions in the 2003 ISN/RPS system for classifying lupus nephritis improves renal outcome predictions

The 2003 International Society of Nephrology/Renal Pathology Society (ISN/RPS) pathological classification system of lupus nephritis specified the importance of vascular damage and indicated this should be included in the diagnostic summary. Few pathological studies of lupus nephritis, however, focus on the patterns of renal vascular involvement. Here we assessed renal vascular lesions in lupus nephritis based on the 2003 ISN/RPS classification system and evaluated their association with clinical and pathological data in a large cohort from a single center in China. Among 341 patients with lupus nephritis, 279 were diagnosed with single or multiple renal vascular lesions that included 253 with vascular immune complex deposits, 82 with atherosclerosis, 60 with thrombotic microangiopathy, 13 with noninflammatory necrotizing vasculopathy, and 2 with true renal vasculitis. Patients with thrombotic microangiopathy had the poorest renal outcome. In multivariate Cox hazard analysis after inclusion of renal vascular lesions, the new chronicity index score became a significantly better independent risk factor for renal outcome (hazard ratio 2.32). Thus, renal vascular lesions are common in lupus nephritis and closely correlate with clinical disease activity and renal outcome. Inclusion of a detailed description of renal vascular lesions in the ISN/RPS classification of lupus nephritis may strengthen its predictive value for renal outcome.

Endothelium-Neutrophil Interactions in ANCA-Associated Diseases

The two salient features of ANCA-associated vasculitis (AAV) are the restricted microvessel localization and the mechanism of inflammatory damage, independent of vascular immune deposits. The microvessel localization of the disease is due to the ANCA antigen accessibility, which is restricted to the membrane of neutrophils engaged in β2-integrin-mediated adhesion, while these antigens are cytoplasmic and inaccessible in resting neutrophils. The inflammatory vascular damage is the consequence of maximal proinflammatory responses of neutrophils, which face cumulative stimulations by TNF-α, β2-integrin engagement, C5a, and ANCA by the FcγRII receptor. This results in the premature intravascular explosive release by adherent neutrophils of all of their available weapons, normally designed to kill IgG-opsonized bacteria after migration in infected tissues.

Evaluation of Clinical Outcomes and Renal Vascular Pathology among Patients with Lupus

The objective of this study was to determine the clinical significance of renal vascular lesions in lupus nephritis. Renal vascular lesions defined as thrombotic microangiopathy, lupus vasculopathy, uncomplicated vascular immune deposits, and arterial sclerosis were evaluated in relation to renal and vascular morbidity and overall mortality. Biopsies from 161 patients revealed thrombotic microangiopathy (13), lupus vasculopathy (5), and arterial sclerosis (93). No renal vascular lesions were found in 24.8% of patients. At the time of biopsy, arterial sclerosis or lupus vasculopathy patients were older (arterial sclerosis=37.9±13.0 and lupus vasculopathy=44.4±8.9 versus controls=33.1±8.9 years, P<0.05), and the mean arterial pressure was higher in all groups compared with controls. Nephritis subtype, activity indices, and proteinuria were similar between groups, estimated GFR was lower in arterial sclerosis (70.5±33.3 versus 84.5±26.6 ml/min per 1.73 m(2), P=0.03), and chronicity index (thrombotic microangiopathy=3.5, lupus vasculopathy=4.5, and arterial sclerosis=2.5) was higher in all renal vascular lesions subgroups versus controls (1.0, P<0.05). In 133 patients with similar follow-up, the association between renal vascular lesions and vascular events was significant (Fisher exact test, P=0.002) and remained so after multivariate analysis (exact conditional scores test, P=0.04), where the difference between arterial sclerosis and uncomplicated vascular immune deposits was most noticeable (odds ratio [95% confidence interval]=8.35[0.98, 83.12], P=0.05). The associations between renal vascular lesions, renal outcomes, and death were not significant, likely because of insufficient power. Renal vascular lesions are common in SLE patients with nephritis and may be associated with arterial vascular events.

True vasculitis in lupus nephritis

Vascular lesions are encountered frequently in renal biopsy specimens of patients with systemic lupus erythematosus (SLE) and can present in a variety of morphologic forms. True renal lupus vasculitis (TRLV) is one of the rare vascular lesions associated with lupus nephritis that has been infrequently reported in the medical literature. The primary focus on glomerular pathology and collective classification of the vascular lesions under lupus vasculopathy is one of the reasons why this form of inflammatory vasculitis has been under-recognized as a separate disease entity. Here we have comprehensively reviewed the literature on renal vascular involvement in SLE for a better understanding of the epidemiology, morphologic features, pathogenesis, clinical course and treatment of TRLV. It can be morphologically differentiated from other forms of renal vascular lesions in lupus nephritis, i.e. arteriosclerosis, uncomplicated vascular immune deposits, non-inflammatory necrotizing vasculopathy, and thrombotic microangiopathy. Despite close similarities with antineutrophil cytoplasmic autoantibody associated vasculitis (AASV), there are certain morphological differences that warrant a thorough investigation of the possible pauci-immune mechanism of pathogenesis. The vasculitis follows a severe clinical course in general with rapid progression to renal failure, although favorable outcomes have been reported in certain cases. The standard use of steroids and cytotoxic drugs has yielded variable results in the treatment of TRLV. Current treatment modalities being used in lupus nephritis and AASV have been compared in this article with focus on drugs acting on the inflammatory cells implicated in TRLV pathogenesis.

Direct immunofluoresence in vasculitic neuropathy: Specificity of vascular immune deposits

In suspected vasculitic neuropathy, vasculitis is demonstrated in only 30% of superficial peroneal nerve (SPN)/peroneus brevis muscle (PBM) specimens. Pathologic predictors of vasculitis are thus needed for non-diagnostic cases. Immune deposits in epineurial vessels have an established sensitivity but unknown specificity. In this study we assessed specificity using direct immunofluorescence (DIF) in SPN/PBM biopsies for suspected vasculitic neuropathy. Biopsies from 13 patients with vasculitis, 13 without vasculitis, and 6 with diabetic radiculoplexus neuropathy (DRPN) were stained for immunoglobulin G (IgG), IgM, and complement 3 (C3), and analyzed in a blinded manner. Vascular immunoglobulin or C3 deposits occurred in 12 of 13 nerve or muscle biopsies (11 of 13 nerves, 5 of 13 muscles) in vasculitis vs. 1 of 13 (1 of 13 nerves, 0 of 13 muscles) in controls (P = 0.00003). Specificity was 92%. For DRPN, vascular immune deposits occurred in 5 of 6 nerves or muscles (4 of 6 nerves, 1 of 5 muscles), similar to vasculitis but significantly different from controls. Epineurial/perimysial vascular deposits of immunoglobulin/C3 by DIF are a specific marker of vasculitic neuropathy.

Renal extraglomerular vascular immune deposits in IgA glomerulonephritis

Kidney biopsies of 425 patients with IgA glomerulonephritis were studied to reveal the incidence, composition and possible clinical significance of extraglomerular vascular immune deposits. IgA deposits were detected in 20 cases, IgM in 28 (in 5 together with IgA), C3 in 317 and no vascular deposits in 60 cases. C3 and IgA deposits were granular, resembling mesangial deposits, while IgM deposits were lumpy, similar to IgM deposits in sclerotic and hyalinized glomeruli. The incidence of vascular lesions in patients with IgA (30%) and C3 deposits (24%) was not significantly higher as compared to those without vascular deposits (20%), but was significantly higher in patients with IgM deposits (68%, P < 0.00004). Only the presence of vascular IgM deposits correlated significantly with severe glomerulosclerosis, arterial hypertension and elevated serum creatinine levels (all P < 0.001). We conclude that neither C3 nor IgA deposits, in spite of their suggested immune complex nature, contribute significantly to the development of vascular lesions. Lumpy IgM deposits, probably the result of insudation of plasma proteins into the blood vessel walls, were associated with advanced vascular lesions and glomerulosclerosis and are probably a part of non-immune mediated progression of IgA glomerulonephritis.

Presence and interpretation of vascular immune deposits in human skin: The value of direct immunofluorescence

Direct immunofluorescence investigation of the skin is an easy and valuable technique to establish the diagnosis immune complex vasculitis. Vascular immune deposits can be found in 60–80% of all cases. Absence of vascular immune deposits, however, does not exclude vasculitis per se, since the dynamics of the vasculitic process limit their presence in time. Knowledge of these dynamics is indispensable for both the clincian and the interpreter. Several practical options are discussed that may increase sensitivity. The specificity of vascular immune deposits has become a complex matter. Different immunoglobulin classes have different specificity, indicating that specificity also depends on the relative incidence of individual immunoglobulin classes. Some of these relative incidences seem to have changed over the years. Furthermore, several non-vasculitic diseases and conditions have now been described, that may show fluorescent pictures similar to vasculitis and thus decrease specificity.

Koebnerization as a cutaneous manifestation of immune complex—mediated vasculitis

Two unusual examples of the cutaneous manifestations of vasculitis are presented. In both cases lesions occurred on previously traumatized skin and on normal skin of the dependent areas. Lesional skin biopsy specimens obtained from the koebnerized sites and from the other dependent sites revealed evidence of vascular injury in both patients. A diagnosis of leukocytoclastic vasculitis was made in one patient and pityriasis lichenoides et varioliformis acuta in the other. Direct immunofluorescence microscopy of lesional skin specimens from both patients demonstrated dermal vascular immune deposits. Raji cell assay detected a significant elevation of circulating immune complexes in the serum of both patients. Neither koebnerizing leukocytoclastic vasculitis nor koebnerizing pityriasis lichenoides et varioliformis acuta has been reported previously.

Histopathologic and immunopathologic study of pyoderma gangrenosum.

Sixty-three patients with pyoderma gangrenosum were seen and studied at the Mayo Clinic from 1971 to 1980. Biopsies from the erythematous border or necrotic edge of the pyoderma gangrenosum lesions usually demonstrated a characteristic pathogenic morphologic evolution. The early lesions revealed mild to moderate perivascular lymphocytic infiltrate associated with endothelial swelling. The fully developed lesions demonstrated necrosis in addition to a dense lymphocytic infiltration surrounding as well as involving the blood vessels. Extravasation of erythrocytes and thrombosis sometimes were seen. Ulceration, infarction, and abscess formation were found in the later stages of evolution. Direct immunofluorescence results were positive in the blood vessels of 36 of 65 (55%) specimens. IgM, C3, and fibrin were found in the papillary and reticular dermal vessels. IgG and IgA were only occasionally present. Pyoderma gangrenosum appears to be a reactive process that is manifested as a vasculitis. Biopsy material from the advancing active erythematous border has early characteristic dermatopathologic findings of lymphocytic vasculitis. Cutaneous vascular immune deposits suggest an immune pathogenesis of either an immune complex disease or lymphocytotoxic reaction.

Cutaneous Deposition of Immune Complexes in Chronic Serum Sickness of Mice Induced with Cationized or Unaltered Antigen

We have previously shown that cationic proteins localize to the dermal-epidermal junction (DEJ) after i.v. injection in experimental animals. In the present studies, cationized rabbit IgG was used as antigen for induction of chronic serum sickness in C57BL/6J mice over a period of 4 weeks. The formation of immune deposits was examined by immunofluorescence microscopy at weekly intervals during chronic antigen administration and at 7 weeks from the initiation of studies. Chronic administration of the cationized antigen led to immune complex deposits at the DEJ, while administration of the same antigen in native form did not lead to these deposits. Junctional immune deposits increased with higher doses of cationized antigen and paralleled renal extraglomular deposition in intensity, persistence, and morphology. Mice given cationized antigen also demonstrated vascular immune complex deposits without complement, while mice given native antigen had complement deposits and developed perivascular inflammation. No inflammation or complement deposition was detected at the DEJ in either group. Charge properties of circulating antigens are important in determining tissue sites of immune complex deposition and inflammation. Circulating cationic antigens can lead to immune deposits at the DEJ.

Simultaneous immunologic studies of skin and kidney in systemic lupus erythematosus clinicopathologic correlations.

Thirty-two biopsies of kidneys and of normal skin were performed simultaneously on patients with systemic lupus erythematosus (SLE) to determine whether the deposition of immune reactants in skin was correlated with the severity of renal injury or with several serologic measures of systemic disease activity. Immunofluorescent deposits at the dermal-epidermal junction (lupus band test) did not correlate with any clinical or histologic measures of glomerulonephritis or with serologic abnormalities. Immune deposits in dermal venules were found in 56% of the skin biopsies and were correlated with hypocomplementemia and higher levels of immune complexes in serum, and possibly with glomerular subendothelial electron dense deposits. Azathioprine therapy was correlated with absence of both sub-epidermal and vascular immune deposits. Immuno-fluorescent findings on serial skin biopsies on 13 patients were highly inconsistent. It is concluded that the lupus band test is clinically useful only as a diagnostic aid but not helpful in assessing renal or serologic activity of lupus, and that dermal vascular deposits of immunoglobulin or complement are more frequent than previoulsy recognized and correlate with measures of circulating immune complexes.

The composition of pulmonary immune deposits in systemic lupus erythematosus

The in vivo complement deposition and in vitro complement reactivity of immune aggregates were studied in the lungs of five patients with systemic lupus erythematosus (SLE). By direct and indirect immunofluorescence, C1q deposition appeared comparable to Ig deposition, but deposition of other complement proteins (C4, C2, C3c, C5, B, P) was scant or absent. In contrast, glomerular and renal vascular immune deposits in these patients showed extensive localization of these complement components. The pulmonary immune aggregates were capable of in vitro complement fixation of C4, C3c, and C5. These studies suggest that complement deposition may be limited at sites of pulmonary immune aggregation in certain patients with SLE, and that factors other than intrinsic complement reactivity appear to be responsible for the observed complement component composition of immune deposits in the lungs of these patients.