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The purpose of this study was to determine the profile of immunoreactants deposited in intact skin biopsies from the patients with confirmed and probable systemic lupus erythematosus. The study involved 94 patients who, along with a standard clinical and laboratory examination, underwent a biopsy of clinically healthy skin in the deltoid muscle area (lupus band test). The nature and combination of immune deposits in the skin, the strength of immunofluorescence, and the location were evaluated. In the patients with significant systemic lupus erythematosus (n = 56), lupus band test was positive in 60.7 % of the cases and correlated with disease activity according to SLEDAI 2K (p = 0.001). At the same time, the skin biopsy often revealed the immunoreactant IgM (85.3 %), the degree of fluorescence of which had direct correlations with the increased level of antibodies to dsDNA (p 0.05). In the examined patients with probable systemic lupus erythematosus, positive lupus band test was detected in 47 % of cases, and IgM was detected in 72.2% of patients, which brought them closer to the group of patients with confirmed systemic lupus erythematosus. However, 33.3% of patients with probable systemic lupus erythematosus had isolated deposits of any one immunoreactant, while the association of immunoreactants (IgM+IgG) and (IgM+IgG+C3) characteristic of confirmed systemic lupus erythematosus occurred in only 27.7 and 5.5% of cases, respectively. It should be noted that the C1q immunoreactant was detected in the skin biopsies with both confirmed (38.2%) and probable systemic lupus erythematosus (39%). The data obtained suggest that lupus band test with the presence of a specific pattern of immunoreactants can be used as an additional diagnostic test for the diagnosis of systemic lupus erythematosus.

Leukocytoclastic vasculitis has been reported in the setting of COVID-19 infection and post-COVID-19 vaccination. We report a case of post-COVID-19 vaccination IgA vasculitis with IgA immune deposits in the skin and renal involvement; SARS-CoV spike protein immunohistochemical staining was negative. IgA vasculitis with skin and renal involvement is a potential reaction to COVID-19 vaccination. This article is protected by copyright. All rights reserved.

Introduction Routine C4d staining in renal transplantation has stimulated its use in kidney biopsies with glomerulonephritis (GN). Methodical description on staining patterns in the native kidney is not available. Methods We retrospectively evaluated C4d staining in formalin-fixed paraffin-embedded sections from 519 native kidney biopsies (bx) with and without glomerular disease. Results Strong C4d staining was consistently present in immune-complex GN, including lupus nephritis (LN) (n = 68), membranous GN (n = 24), membranoproliferative glomerulonephritis (MPGN) pattern (n = 22), fibrillary GN (n = 3), and proliferative GN with monoclonal IgG (n = 3). C4d stained all cases of postinfectious GN (n = 7) amyloidosis (n = 20) and C1q GN (n = 3). In contrast, IgA nephropathy (IgAN) (n = 34), was negative in 62% of bx, with the rest staining variably. The E1 Oxford classification score correlated with capillary wall C4d staining (P = 0.05). C4d marked the glomerular and arteriolar lesions in thrombotic microangiopathy (TMA; n = 16), the glomerular sclerotic segments in focal segmental glomerulosclerosis (FSGS; n = 77), and marked areas of necrosis in crescentic GN (n = 21). In diabetic glomerulopathy (n = 70), C4d marked advanced insudative lesions but was negative otherwise. C4d weakly stained the mesangium, or was negative in normal biopsies (n = 13), minimal change disease (MCD; n = 21), thin basement membrane disease (n = 20), Alport (n = 3), IgM nephropathy (n = 2), C3 glomerulopathy (n = 5), acute interstitial nephritis (n = 12), acute tubular necrosis (n = 22), ischemic glomerulopathy/nephrosclerosis (n = 23), and other miscellaneous processes (n = 14). Staining in tubular basement membranes and peritubular capillaries was most common in lupus. Conclusion Based on reliable staining in lupus and membranous GN, C4d staining is potentially useful as a screening and diagnostic tool, if only paraffin-embedded tissue is available. Knowledge of C4d staining patterns in normal and pathological tissues enhances its diagnostic value., Graphical abstract

BACKGROUND AND OBJECTIVES: The neural EGF-like 1 (NELL-1) protein is a novel antigen in primary membranous nephropathy. The prevalence and clinical characteristics of NELL-1–positive membranous nephropathy in Chinese individuals with primary membranous nephropathy are unclear. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A total of 832 consecutive patients with biopsy-proven primary membranous nephropathy were enrolled. The glomerular expression of phospholipase A2 receptor (PLA2R) and thrombospondin type 1 domain-containing 7A (THSD7A) was screened. Glomerular immunohistochemistry staining for NELL-1 was performed in 43 patients with PLA2R- and THSD7A-negative membranous nephropathy, 31 patients with PLA2R-positive membranous nephropathy, and two patients with PLA2R and THSD7A double positivity. The NELL-1 antibody was also detected in the sera of patients with NELL-1–positive membranous nephropathy by western blot. Clinical and pathologic features were comparable between patients with isolated NELL-1–positive, isolated PLA2R/THSD7A-positive, and triple antigen–negative membranous nephropathy. RESULTS: Among the 832 patients with primary membranous nephropathy, 11 of 54 (20%) patients with PLA2R-negative membranous nephropathy had THSD7A-positive membranous nephropathy. NELL-1–positive membranous nephropathy accounted for 35% (15 of 43) of all patients with PLA2R- and THSD7A-negative membranous nephropathy. One patient was double positive for NELL-1 and PLA2R in glomerular deposits and positive for only the PLA2R antibody in the serum. Most patients with NELL-1–positive membranous nephropathy were women. No tumors were found. There were significant differences in the prevalence of IgG subtypes between patients with different antigen positivity. Among patients with isolated NELL-1–positive membranous nephropathy, although 80% (12 of 15) were IgG4 staining positive, the proportion of IgG4 dominance was only 67% (ten of 15). CONCLUSIONS: About one third of patients who were PLA2R and THSD7A negative were NELL-1 positive in Chinese patients with primary membranous nephropathy. NELL-1–positive membranous nephropathy was more common than THSD7A-positive membranous nephropathy in PLA2R-negative membranous nephropathy.

BackgroundRapidly progressive glomerulonephritis caused by antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is typically characterized as pauci-immune glomerulonephritis. However, immune complex (IC) deposition in the glomerulus has been reported in a growing number of studies. Here, we assess the presence of glomerular immune deposits alongside renal outcome in myeloperoxidase (MPO)-ANCA associated glomerulonephritis (MPO-ANCA GN).MethodsClinical and histopathologic characteristics of 97 patients with MPO-ANCA GN classified by renal biopsy from January 2008 to December 2019 were extracted retrospectively from electronic medical records. The extent of immune deposits in the kidney (C3, C4, C1q, IgA, IgG, IgM) at diagnosis were analyzed by immunofluorescence (IF). Patients were followed up for a median period of 15 months. The response to treatment and outcomes of renal and histological lesion changes were also assessed.ResultsIn our study, 41% (40/97) of patients showed positive IF (≥2+) for at least one of the six immunoglobulin or complement components tested. Patients with IC deposits showed higher levels of serum creatinine (p=0.025), lower platelet counts (p=0.009), lower serum complement C3 (sC3) (≤790 ml/L) (p=0.013) and serum IgG (p=0.018) than patients with pauci-immune (PI) deposition at diagnosis. End-stage renal disease was negatively associated with eGFR (HR 0.885, 95% CI 0.837 to 0.935, pConclusionIn conclusion, patients with immune complex deposits in the kidney showed less platelet count, lower sC3 and sIgG levels, and higher serum creatinine levels. Patients with low sC3 at initial and with continued low sC3 during the treatment displayed a trend toward poorer kidney survival. Moreover, the IC group showed a worse renal outcome than the PI group, further enforcing the present strategy of introducing complement targeted therapies in AAV.

Introduction Immunoglobulin A vasculitis (IgAV) is a small-vessel vasculitis with IgA-dominant immune deposits. IgAV frequently involves the skin, gastrointestinal tract, joints and kidneys. In contrast to other types of small-vessel vasculitis, IgAV is rarely complicated by intra-alveolar haemorrhage (IAH). Methods/Results We describe a patient with relapsing bladder cancer who presented with IAH during the course of IgAV successfully treated with corticosteroids alone. Conclusion This case report reminds us that IgAV can manifest with IAH. There are no robust data to support the systematic use of cyclophosphamide or plasma exchange as first-line therapy for IgAV with IAH. LEARNING POINTS Intra-alveolar haemorrhage in IgA vasculitis is an uncommon but important condition. The treatment strategies for IgA vasculitis and intra-alveolar haemorrhage and their rare association are discussed with reference to the literature.

Background The immune regulatory properties of semaphorin3A (sema3A) (both innate and adaptive) are well established in many in-vitro studies. When sema3A was incubated with active B cells from SLE patients, it could efficiently reduce the expression of TLR-9 in correlation with a significant reduction of relevant auto-antibodies. The injection of sema3A to a mice model of rheumatoid arthritis was proven to be highly beneficial, both in attenuating clinical symptoms and in decreasing inflammatory mechanisms. Objectives This study was designed in order to assess possible therapeutic benefits following the injection of sema3A to NZB/W mice. Results The injection of sema3A to young mice (at week 12) before disease onset, delayed the appearance of proteinuria. Here, the median time to severe proteinuria was 110 days, 95% CI: 88 to 131. However, in mice in which empty vector was injected, median time to severe proteinuria was 63 days, 95% CI: 0 to 139). Sema3A treatment, reduced significantly renal damage, namely, it prevented the development of immune deposits in the glomeruli. When sema3A was injected at the onset of proteinuria, aiming to treat rather than to prevent disease in these mice, survival was significantly increased and the deterioration of proteinuria was significantly delayed. Conclusion Semaphorin3A is highly beneficial in reducing lupus nephritis in NZB/w mice. It delays the appearance and deterioration of proteinuria, and increases survival rates in these mice. Further studies will establish the idea of applying sema3A in the treatment of lupus nephritis.

Recently, a number of reports have described dominant C3 deposits in renal biopsies of patients with infection-related glomerulonephritis (GN). While acute post-infectious GN and membranoproliferative GN are commonly characterized by immune deposits containing C3 and/or C4, the absence of immunoglobulin (Ig) and/or immune complexes at light or electron microscopy is a rather unusual observation. Dominant C3 deposition is believed to result from the alternative pathway of complement activation via the C3bBb "tickover" convertase. The actual occurrence of C3 glomerulopathy could be underestimated, since infection-related GN often quickly subsides without the need for a renal biopsy. A more thorough understanding of the pathways that lead to complement assembly and deposition within the kidney is needed to support a new classification of complement-related lesions, including entities such as dense deposit disease, (atypical) hemolytic-uremic syndrome, dominant C1q, CFHR5, C4d, and C3 glomerulopathies. We will briefly review recent work in this area, focusing on GN with selective complement C3 deposits.

Background: It has been postulated that periodic acid–Schiff staining of basement membrane can predict direct immunofluorescence patterns seen in epidermolysis bullosa acquisita and bullous pemphigoid. It has also been suggested that the type of inflammatory infiltrate or presence of fraying of basal keratinocytes may differentiate these two conditions. Objective: In this study, we aimed to confirm these observations. Methods: We reviewed 13 cases of direct immunofluorescence-confirmed epidermolysis bullosa acquisita and 19 cases of direct immunofluorescence-confirmed bullous pemphigoid, all with a subepidermal blister in the routinely processed specimen. The gold standard for diagnosis of epidermolysis bullosa acquisita vs bullous pemphigoid was taken to be identification of immune deposits on the dermal side (‘floor’ for epidermolysis bullosa acquisita) or the epidermal side (‘roof’ for bullous pemphigoid) of the salt-split direct immunofluorescence specimen. Our tests to distinguish epidermolysis bullosa acquisita from bullous pemphigoid on the routinely processed biopsy included periodic acid–Schiff basement membrane on the blister roof, neutrophilic infiltrate, lack of eosinophilic infiltrate, and absence of keratinocyte fraying. Results: Sensitivity and specificity for each test were as follows: periodic acid–Schiff staining of roof (sensitivity 25%, specificity 95%), neutrophilic infiltrate (sensitivity 54%, specificity 74%), lack of eosinophilic infiltrate (sensitivity 92%, specificity 68%), and absence of keratinocyte fraying (sensitivity 62%, specificity 58%). Conclusions: Features in the routinely processed biopsy were unable to reliably distinguish between epidermolysis bullosa acquisita and bullous pemphigoid. Direct immunofluorescence on salt-split skin remains the standard for differentiation.

Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) is a newly recognized entity caused by monoclonal deposition of IgG. PGNMID resembles immune complex glomerulonephritis (GN) on light and electron microscopy. The monotypic immunoglobulin deposits seen on immunofluorescence (IF) clinches the diagnosis. We report a case of proliferative GN associated MGRS and review the relevant literature. The patient had significant proteinuria and elevated serum creatinine. The renal biopsy showed proliferative GN with focal crescents and monoclonal immune deposits confirming a diagnosis of PGNMID. Serum work up showed no monoclonal proteins. Proliferative GN as a manifestation of a monoclonal gammopathy needs to be borne in mind especially in renal biopsies of older patients.

Glomerulonephritis (GN) due to infective (primarily bacterial) endocarditis is well documented with the most common lesions being necrotising and crescentic GN, followed by endocapillary proliferative GN. Prominent C3 staining and subepithelial immune deposits on electron microscopy are commonly

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease associated with autoantibodies directed against two components of junctional adhesion complexes in stratified epithelia, BPAG2 and BPAG1-e. BP typically develops in the elderly and manifests with widespread eczematous, urticated and bullous lesions. In up to 20% of the affected patients, obvious blistering is lacking and the clinical features of BP are misleading and closely mimic a variety of other inflammatory conditions. Diagnosis of BP, which should be rather called cutaneous pemphigoid, relies on direct immunofluorescence microscopy studies to detect tissue-bound IgG and/or C3 immune deposits along the epidermal basement membrane zone. Here, the clinical presentations of BP and the diagnostic algorithm with the immunopathological studies available to classify affected patients are reviewed. Finally, the need for widely accepted criteria for the classification of BP patients is emphasized, since in a number of patients with featu...

Background: Relapse or worsening of nephrotic syndrome (NS) in idiopathic membranous nephropathy (IMN) is generally assumed to be due to recurrent disease. Here we document that often that may not be the case. Subjects and Methods: This is a prospective study of 7 consecutive IMN patients whose renal status improved, then worsened after completing a course of immunosuppressive therapy. Each underwent detailed testing and repeat kidney biopsy. Results: In 4 patients (group A), the biopsy showed recurrent IMN (fresh subepithelial deposits). Immunosuppressive therapy was begun. In the other 3 patients (group B), the biopsy showed that the deposits had been eradicated. However, the glomerular basement membrane (GBM) was thickened and vacuolated. Immunosuppressive therapy was withheld. Groups A and B were comparable except that group B had very high intakes of salt and protein, based on 24-hour urine testing. Reducing their high salt intake sharply lowered proteinuria to the subnephrotic range and serum creatinine stabilized. Conclusion: This work is the first to demonstrate that relapse/worsening of NS can occur in IMN even though the GBM deposits have been eradicated. High salt and protein intake in combination with thickened and vacuolated GBM appears to be the mechanism.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis is considered a “pauci-immune” disease, characterized by absent or mild glomerular tuft staining for immunoglobulin and/or complement. We describe a 72-year-old man with progressive renal failure over five months who was found to have P-ANCA associated crescentic glomerulonephritis. Renal biopsy also revealed immunofluorescence staining for Immunoglobulin G and C3. Treatment comprised corticosteroids, cyclophosphamide, and plasmapheresis but unfortunately kidney function did not recover, likely due to substantial interstitial fibrosis at diagnosis. This case illustrates that serologic evaluation for ANCAs should not be discounted when immune deposits are present. Prompt diagnosis is warranted.

Joint tissue from 7 patients with severe Factor VIII deficiency was examined for immune deposits. Tissue was obtained from fresh surgical specimens and offered information from patients treated by a variety of methods. No immune deposits were located, and in spite of others' suggestions that immune phenomena are occurring in the plasma of patients with hemophilia, no evidence for immune damage appeared in the joint tissues from these patients with hemophilic arthropathy.

Thirty silent lupus nephritis (SLN) patients were compared to 16 individuals bearing overt lupus nephritis (OLN). Results included: years of systemic lupus erythematosus (SLE) diagnosis were significantly earlier (4.6 ± 2.8 years) in SLN than in OLN (7.18 ± 3.61) ( P < 0.05). Neurological compromise, hypertension, normocitic anemia and lymphopenia were significantly prevalent in OLN than in SLN ( P < 0.05). Beside normal urinary sediment and renal function tests, the SLN group showed a moderate increase of both activity (AI) and chronicity (CI) renal pathology index when compared to highly increased AI and CI in OLN ( P < 0.05). Seventy percent of SLN patients were ISN/RPS Classes I (6.6%) and II (63.3%) while 81% of OLN cases were Classes III, IV (37.5%) and V. IgG, IgA, IgM, λchain, C3 and fibrinogen immune deposits were found in 90% or over in both SLN and OLN individuals while in 60% or over, both groups also showed K chain, C1q and C4 deposits. While prevalence of ANA, anti-dsDNA and anti-C1q antibodies were similar in both groups, anti-histone, anti-RNP, CIC and CH50serum levels were significantly different in OLN versus SLN ( P < 0.05). We strongly suggest that indeed SLN is the earliest stage in the natural history of lupus nephritis.

Immunofluorescence is an immunohistochemical method used to demonstrate the presence of antigen and antibodies in the tissues or serum. It is an auxiliary diagnostic tool for the autoimmune bullous and inflammatory disorders. It detects the in situ and circulating immune deposits that are involved in the pathogenesis of immunobullous diseases.

Antibodies to human myeloperoxidase and cathepsin G have been detected in the serum of some patients with systemic lupus erythematosus. Therefore, the presence of antibodies to human myeloperoxidase and cathepsin G was examined in glomerular immune deposits. Glomerular basement membrane fragments were prepared from renal tissues obtained at autopsy from 19 patients with systemic lupus erythematosus. IgG was extracted from the glomerular basement membrane fragments and tested with sensitive immunoassays for antibodies to myeloperoxidase and cathepsin G. Antibodies to cathepsin G were not detected in the extracts but antibodies to human myeloperoxidase were found in extracts of one specimen. In the extract with 6M guanidine hydrochloride these antibodies were enriched 103-fold, compared to the initial supernatant of glomeruli, which served as a serum surrogate. The recovered antibodies to myeloperoxidase accounted for 12% of the recovered IgG. These findings add autoantibodies to human myeloperoxidase to the list of antibodies that have been shown to be present in glomerular immune deposits of patients with lupus glomerulonephritis.

For nearly 100 years, pathologists have utilized "special histochemical stains" to assist in tissue-based diagnosis. As illustrated in Figures 1 and 2, histochemical stains have been used to identify infectious microorganisms (e.g., Mycobacterium tuberculosis with acid-fast bacillus (AFB) stain), to detail inflammatory stromal or structural alterations (e.g., fibrosis in liver cirrhosis with Masson trichrome), to identify microanatomic sites of disease (e.g., basement membrane in glomerulonephritis with Jones methenamine silver), to identify abnormal chemical deposits (e.g., iron in hemochromatosis with Prussian blue stain), or abnormal immune deposits (e.g., amyloid via Congo red stain). The current surgical pathology laboratory may employ a repertoire of 20 to 25 "special stains" to ensure the full diagnostic complement. While the diagnostic repertoire and the biochemical recipes for the stains are now a well-established, codified part of surgical pathology, there is an ever-moving, leading edge of new developments including new reagents, applications, and methods. This review seeks to update the reader on some of the new applications including both new reagents and methods. Particular emphasis will be placed on the recent technologic advance of automating special stains in kinetic-mode (1-4). The authors consider in turn: 1. In brief, the "news" (recent literature review) of new staining applications; 2. In greater detail, two new applications for detection of Microsporidia and Helicobacer pylori; 3. The new technologic advancement of kinetic mode automation of special stains.

In a time-study of active Heymann nephritis, the expression of agrin, the main heparan sulfate proteoglycan in the glomerular basement membrane, was analyzed in relation to deposition of IgG and complement in the glomerular capillary wall and the development of albuminuria. Binding of IgG autoantibodies to the glomerular capillary wall could be detected from 2, wk onward, followed by activation of complement after 6 wk. progressive albuminuria developed from 6 wk onward to a level of 274 +/- 68 mg/18 h at week 12. The staining intensity for the agrin core protein decreased slightly, and the staining intensity for the heparan sulfate stubs that were still attached to the core protein after heparitinase digestion remained normal. From week 6 onward, however, a progressive decrease was seen in the staining of two monoclonal antibodies (mAb) directed against different epitopes on the heparan sulfate polysaccharide side chain of agrin (to 35 and 30% of the control level, respectively, at week 12, both mAb P = 0.016). Moreover, albuminuria was inversely correlated with heparan sulfate staining as revealed by these antibodies (r(s) = -0.82 and r(s) = -0.75, respectively, both mAb P

The immunoperoxide (IP) technique can be used for the detection of immune deposits in various tissue pathologies. This article focusses on the standardization of the reagents anti IgG, anti IgA and anti C3C which are used to target these immune deposits. Lymph node tissue was used as substrate for standardization of anti IgG and anti IgM. For anti IgA, intestine was used while for anti C3C kidney tissue rapidly proliferating glomerulo nephritis - RPGN was utilized. Sensitivity of the technique was found to be high. Also the results on paraffin section were excellent and could be interpreted using simple light microscope. It is concluded that once standardization is achieved, IP can be used as an essential modality in the detection of immune deposits in a wide variety of immunologically mediated dermatologic disorders.

Antineutrophil cytoplasmic antibodies (ANCA) constitute a family of auto-antibodies directed against various components of the neutrophil cytoplasm. Their identification and association with vasculitis and rapidly progressive glomerulonephritis has led to considering these diseases as possible autoimmune disorders. In addition, ANCAs constitute a diagnostic tool and a guideline for therapy during follow-up. Originally identified by Davies et al. in 1982 in 8 patients who had necrotizing glomerulonephritis but no immune deposits or systemic vasculitis (1), ANCA are now regarded as a serological marker for active pauci-immune necrotizing and crescentic glomerulonephritis, either in their renal-limited form or associated with systemic vasculitis such as Wegener's granulomatosis (WG), microscopic polyangiitis (mPA), and Churg-Strauss syndrome (CSS) (2-9). The usefulness of ANCA detection for the diagnosis of these forms of vasculitis is now established but its usefulness on follow-up remains disputed (10-13). Two major ANCA antigens have already been identified. Proteinase 3 (PR3) in a serine protease of 29 kDa initially identified by Kao and producing a cytoplasmic staining pattern termed cANCA by indirect immunofluorescence (IIF) (14,15). Myeloperoxidase (MPO) is another myeloid lysosomal enzyme producing an artefactual perinuclear staining of ethanol-fixed neutrophils termed pANCA (2,16). Both are localized in the azurophilic granules of neutrophils and monocytes, are translocated to the cell surface during cell activation (17), and are able to interact directly with ANCA. Despite this common location, MPO and PR3 are associated with a broad spectrum of clinical conditions.

Henoch-Schonlein purpura (HSP) is a small vessel vasculitis with immunoglobulin A-dominant immune deposits found in vessel walls. It primarily affects children, is uncommon in adults and often under-recognised in the elderly population due to its rarity in this group. When a purpuric rash develops in an older person it is typically treated with antibiotics for presumed infection, rather than investigated as potentially HSP. It is important to recognise this condition, particulary in older adults, as diagnosis has implications for management and prognosis. We report a case of vasculitis with renal involvement in an older person.

Primary membranous nephropathy is a common glomerular disease characterized by sub-epithelial immune deposits that has become the prototype of an autoimmune glomerular disease. The purpose of this review is to highlight recent advances regarding the pathogenesis of membranous nephropathy as well as potential new therapies.The discovery of two major podocyte antigens, neutral endopeptidase (NEP), involved in rare cases of neonatal membranous nephropathy, and the M-type phospholipase A2 receptor 1 (PLA2R1), the first antigen discovered in adults, have been major 'breakthroughs' in our understanding of the pathogenesis of human membranous nephropathy. Anti-PLA2R antibodies appear to predict activity of the disease as well as response to therapy. Pediatric and adult cases of membranous nephropathy occurring in the presence of circulating cationic bovine serum album (BSA) and anti-BSA antibodies have also been described, raising the possibility that food antigens may be involved in the development of membranous nephropathy. Moreover, the results of genetic susceptibility have become available. Exciting progress has also been made in the treatment of this disease including therapy with adrenocorticotropic hormone and rituximab.Understanding disease pathogenesis is crucial in guiding patient evaluation and designing appropriate therapy. Recent discoveries have helped to elucidate the pathophysiology of membranous nephropathy and may facilitate a more patient-specific treatment approach in these patients.

It is apparent that significant progress has been made in the characterization of gp330 in the years that have elapsed since its initial identification as the nephritogenic antigen of Heymann nephritis. However, there are still many gaps in our knowledge and we do not yet have a full picture of the molecular events leading to the formation of immune deposits in glomerular capillaries. Moreover, we still do not have direct information on the normal function(s) of gp330 and RAP and their trafficking in renal and other epithelia. The availability of the yolk sac and other cell lines that express gp330 and RAP together with the identification of the functional domains of RAP should greatly facilitate experimental studies designed to elucidate these problems. Progress will also be greatly facilitated in the future when the complete amino-acid sequence of gp330 becomes available, making possible further structural studies. It is our hope that new knowledge obtained on the molecular mechanisms of HN will provide insights into the molecular pathogenesis of human membranous nephropathy and will provide a strategy for the design of appropriate treatments to interrupt the process.