Effectiveness of Nasolabial Flap Versus Paramedian Forehead Flap for Nasal Reconstruction: A Systematic Review and Meta-analysis.

BACKGROUND: Different studies performed on nasal subunit reconstruction by either the nasolabial flap or the paramedian forehead flap have reported contradictory outcomes and complications, claiming one flap or the other as superior. This inconsistency has led to a gap in existing literature regarding the preferable flap for nasal reconstruction. Our aim was to statistically evaluate and compare these two flaps for nasal reconstruction, in terms of subunit preference, complications, and outcomes, using data from previous studies. METHODS: This systematic review is reported using PRISMA protocol and was registered with the International prospective register of systematic reviews. The literature search was done using "paramedian forehead flap", "nasolabial flap", "melolabial flap", "nasal reconstruction". Data regarding demography of study and population, subunit reconstructed, complications, and aesthetic outcomes were extracted. Meta-analysis was performed using MetaXL and summary of findings using GRADEpro GDT. RESULTS: Thirty-eight studies were included, and data from 2036 followed-up patients were extracted for the review. Meta-analysis was done on data from nine studies. Difference in alar reconstruction by forehead versus nasolabial flap is statistically significant [pooled odds ratio (OR) 0.3; 95% CI 0.01, 0.92; p = 0.72; I2 = 0%, n = 6 studies], while for dorsum and columella reconstruction the difference is not statistically significant. Risk of alar notching is marginally more in forehead flap, however difference in incidence of partial/complete flap necrosis, alar notching and hematoma/bleeding among the flaps is not statistically significant. CONCLUSION: Alar reconstruction is preferred by nasolabial flap. Complications are similar in both groups. Comparison of aesthetic outcome needs further exploration. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Donor Finger Morbidity in Cross-Finger Flap: A Systematic Review and Meta-Analysis.

Background The morbidity of donor finger in a cross-finger flap has not received as much importance as the outcomes of the flap itself. The sensory, functional, and aesthetic morbidity of donor fingers, reported by various authors, are often contradictory to each other. In this study, objective parameters for the sensory recovery, stiffness, cold intolerance, cosmetic outcome, and other complications in the donor fingers, reported in the previous studies, are systematically evaluated. Methods This systematic review is reported using Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) protocol and was registered with the International prospective register of systematic reviews (PROSPERO registration no. CRD42020213721). Literature search was done using "cross-finger," "heterodigital," "donor finger," and "transdigital" words. Data regarding demography, patients' number and age, follow-up duration and outcomes of donor finger, including 2-point discrimination, range of motion (ROM), cold intolerance, questionnaires, etc. were extracted from included studies. Meta-analysis was performed using MetaXL and risk of bias was evaluated using Cochrane risk of bias tool. Results Out of the total 16 included studies, 279 patients were objectively evaluated for donor finger morbidity. Middle finger was most frequently used as donor. Static two-point discrimination seemed to be impaired in donor finger in comparison to contralateral finger. Meta-analysis of ROM suggested that statistically there is no significant difference in ROM of interphalangeal joints in donor and control fingers (pooled weighted mean difference: -12.10; 95% confidence interval: -28.59, 4.39; I2 = 81%, n = 6 studies). One-third of donor fingers had cold intolerance. Conclusion There is no significant effect on ROM of donor finger. However, the impairment that seems to be in sensory recovery and aesthetic outcomes needs to be further evaluated objectively.

Difference between Capillary Blood Glucose of Free Flap and the Patient: A Novel Objective Marker of Free Flap Vascular Compromise during Postoperative Monitoring.

Background Defining cut-off values of flap glucose levels in diagnosing free flap vascular compromise, without taking patients' glucose levels into account, does not hold good in all circumstances, especially in cases of high fluctuations in patients' capillary blood glucose and in diabetic patients. The aim of our study was to establish the role of capillary blood glucose measurements of the flap in relation to patients' fingertip, as an objective tool for postoperative free flap monitoring. Methods A total of 76 free flaps underwent postoperative monitoring with reference test (clinical parameters) and simultaneously with our index test (difference between capillary blood glucose of free flap and the patient), in non-diabetic and diabetic patients. Patients' demography and flap characteristics were also recorded. An ROC curve was plotted to determine diagnostic accuracy and cut-offs of the index test in diagnosing free flap vascular compromise. Results Our Index test has a cut-off value of 24.5 mg/dL with 68.75% sensitivity and 93% specificity, with an accuracy of 91.54%. Conclusion The difference between capillary blood glucose of free flap and the patient is simple, feasible, and inexpensive, and can be done by any health care professional and does not require any specialized facilities or training. It has an excellent diagnostic accuracy to detect impending free flap vascular compromise, especially in non-diabetics. Although in diabetics, this test becomes less accurate. Being an observer-independent objective test, the difference in capillary blood glucose of patient and flap measurement can be used as a highly reliable tool for postoperative free flap monitoring.

Folic acid-mediated fibrosis is driven by C5a receptor 1-mediated activation of kidney myeloid cells.

We have previously reported that increased expression and activation of kidney cell complement components play an important role in the pathogenesis of renal scarring. Here, we used floxed green fluorescent protein (GFP)-C5a receptor 1 (C5aR1) knockin mice (GFP-C5ar1fl/fl) and the model of folic acid (FA)-induced kidney injury to define the cell types and potential mechanisms by which increased C5aR1 activation leads to fibrosis. Using flow cytometry and confocal microscopy, we identified macrophages as the major interstitial cell type showing increased expression of C5aR1 in FA-treated mice. C5ar1fl/fl.Lyz2Cre+/- mice, in which C5aR1 has been specifically deleted in lysozyme M-expressing myeloid cells, experienced reduced fibrosis compared with control C5ar1fl/fl mice. Examination of C5aR1-expressing macrophage transcriptomes by gene set enrichment analysis demonstrated that these cells were enriched in pathways corresponding to the complement cascade, collagen formation, and the NABA matrisome, strongly pointing to their critical roles in tissue repair/scarring. Since C5aR1 was also detected in a small population of platelet-derived growth factor receptor-ß+ GFP+ cells, we developed C5ar1fl/fl.Foxd1Cre+/- mice, in which C5aR1 is deleted specifically in pericytes, and found reduced FA-induced fibrosis. Primary cell cultures of platelet-derived growth factor receptor-ß+ pericytes isolated from FA-treated C5ar1fl/fl.Foxd1Cre+/- mice showed reduced secretion of several cytokines, including IL-6 and macrophage inflammatory protein-2, compared with pericytes isolated from FA-treated control GFP-C5ar1fl/fl mice. Collectively, these data imply that C5a/C5aR1 axis activation primarily in interstitial cells contributes to the development of renal fibrosis.NEW & NOTEWORTHY This study used novel green fluorescent protein C5a receptor 1 floxed mice and the model of folic acid-mediated kidney fibrosis to demonstrate the pathogenic role of increased expression of this complement receptor on macrophages.

Nonvenomous Snakebite in Pediatric Age Group-Wolf under a Sheep's Coat.

Nonvenomous snakebite, far outnumbering venomous bites, is a neglected occupational hazard in the Indian subcontinent. We encountered four cases of traditionally nonvenomous snakebite in pediatric age group with symptoms of limb swelling proximal to the bite site. All cases were found to have extensive fibrinous exudate and fibrinoid necrosis of the deeper layer of fat, deep to the intact skin and superficial layer of fat, extending far from the wound toward the proximal limb in continuity. This obscured presentation of infection and extensive necrosis of only the deeper layer of fat warrants exploratory incisions proximally for thorough debridement, underlying the normal appearing skin.

The Impact of "COVID-19" and "Webinar Pandemic" on Plastic Surgery Practice in Teaching Institutes and Resident Training-A Multicentric Perspective.

Introduction The study was carried out to quantify the changes induced by the pandemic in plastic surgery practice and training and to study the impact of the webinars on plastic surgery education from a residents' perspective. Methods In this multicentric study, the number and type of surgeries, cause of injuries, and their regional variation during the coronavirus disease 2019 (COVID-19) period (February-September 2020) were compared with pre-COVID-19 time. An online survey on the impact of webinars was conducted for plastic surgery trainees across the country. Results There was a significant reduction in total number of surgeries ( p = 0.003). The procedures for hand ( p = 0.156), faciomaxillary injuries ( p = 0.25), and replantations ( p = 0.46) were comparable; there was a significant reduction in combined orthopedic-plastic-surgical procedures ( p = 0.009) during the pandemic. There was a significant reduction in road accidents ( p = 0.007) and suicidal injuries ( p = 0.002) and increase in assault ( p = 0.03) and domestic accidents ( p = 0.01) during the COVID-19 period. A usefulness score of >8 was given for the webinars by 68.7% residents. There was no significant difference in perception of utility when correlated with the academic program at their institutes ( p = 0.109); 92% opined webinars should continue in post-COVID times. Conclusion There was a drastic reduction in number of elective and emergency procedures during the COVID-19 time, negatively affecting resident training program. Majority of residents felt that webinars could prove a useful adjunct to training in formal training program in post-COVID-19 scenario.

Reconstruction of a Large Traumatic Medial Cheek Defect Using an Anterior-Based Subcutaneous Cervicofacial Rotation Advancement Flap.

In this article, we describe reconstruction of a large left-side medial cheek defect in a 78-year-old woman using a cervicofacial rotation advancement flap. To our knowledge, this is the second case of reconstruction of a large traumatic medial cheek defect using an anterior-based subcutaneous cervicofacial rotation advancement flap that has ever been reported. We applied retention sutures at the level of the jawline and zygomatic eminence using 3-0 nonabsorbable sutures between the subcutaneous tissue of the flap and the periosteum. Despite the limitation of having partially injured adjacent tissue available for reconstruction, meticulous dissection together with skilled postoperative nursing care yielded a good aesthetic outcome in this case.

Large sternal exostoses presenting as stridor: A surgical and anesthetic challenge.

BACKGROUND AND AIMS: Large osteochondroma arising from chest wall and sternum is uncommon and presentation with airway compression is further uncommon. METHODS: Here we present a case of large chest wall osteochondroma as a part of hereditary multiple exostoses in a 9-year-old boy presented with a history of stridor and shortness of breath. The bony mass of the right chest wall was extending up to a suprasternal notch and compressing the trachea. RESULTS: The case was successfully managed by initial femoro-femoral cardiopulmonary bypass under local anesthesia before the induction of anesthesia to prevent respiratory collapse, followed by debulking surgery was done.

Assessment of Clinical and Histological Changes in the Skin Paddle of Pectoralis Major Myocutaneous Flap in Intraoral Reconstruction: A Prospective Cohort Study.

PURPOSE: This study was carried out to characterize the clinical and histological changes in the cutaneous portion of the transferred pedicled pectoralis major myocutaneous flaps used in intraoral reconstruction in patients with head and neck malignancy. METHODS: This was a prospective cohort study carried out from July 2016 to 2018. All patients underwent ablative surgery for oropharyngeal cancers and primary reconstruction with pedicled pedicled pectoralis major myocutaneous flaps. The intraoral flaps were examined for color, texture, presence of hair, chronic inflammatory changes, and ulceration. At 12 months, incisional biopsies were taken from the skin paddle of the intraoral flap and contralateral normal buccal mucosa, and flap histology was compared with that of the contralateral buccal mucosa. RESULTS: Twenty patients were included in the final analysis (M/F, 4:1; mean ± SD age, 51.38 ± 6.76 years). Fourteen flaps resembled oral mucosa, 3 had a mixed appearance of both skin and mucosa, and 3 had appearance of normal skin at 1 year follow-up. The epidermis and stratum corneum were retained in all the flap biopsies; however, severe attenuation was noted in 7 patients (had mucosal appearance) but was significantly different from oral mucosa(P = 0.0003). Cutaneous appendages were found in all the flap epithelia. Thirteen flaps showed grossly attenuation, of which 11 patients had a gross appearance resembling oral mucosa and 2 had a mixed appearance. The biopsies showed varied degree of chronic changes like desquamation in around 35% (7 patients), hyperkeratosis in 35% (7 patients), and chronic candidiasis in 30% (6 patients). CONCLUSIONS: Although the intraorally transferred flaps demonstrate a morphological appearance similar to oral mucosa, there is a histological preservation of skin elements and architecture.

Finger pulp reconstruction with thenar flap: Aesthetic and functional outcome.

PURPOSE: Fingertip injuries are common in industrial production activities as well as in domestic work. Loss of pulp hampers daily life activities. Functional and aesthetic aspects are important in fingertip reconstruction. The bone is usually exposed along with soft tissue loss. Therefore to reconstruct the pulp flap with adequate bulk is required. METHODS: We reported a case series of 12 patients with the injury over the volar aspect of distal phalanx of the index or middle finger. In all cases, laterally based thenar flap was chosen. The flap donor site was closed primarily in most of cases, while 4 patients required skin graft. The flap was detached between 2-3 weeks. Functional assessment was done using static and dynamic 2-point discrimination and range of motion at each joint. The aesthetic outcome was assessed through questionnaire. The results were analyzed using the unpaired t-test (SPSS version 21). RESULTS: Partial necrosis occurred in 2 cases while rest of flaps survived successfully. Static 2-point discrimination ranged from 6-10 mm, mean 8.6 mm; and dynamic 2-point discrimination ranged from 8-10 mm, mean 8.9 mm. The mean satisfaction score was (4.0 ± 0.55). CONCLUSION: Thenar flap is a good choice for reconstruction of the finger pulp as it provides the bulk with good functional and aesthetic outcome.

Two-staged reverse sural flap: a versatile flap with consistent results in the soft tissue reconstruction of distal leg and heel defects-an institutional experience.

BACKGROUND: Reverse sural flap (RSF) is commonly used for soft tissue reconstruction of distal leg and heel defects. The classic method of flap transfer is the single-staged cutaneous islanded reverse sural flap (SS-RSF). This method is associated with variable flap complications notably the venous congestion. The other form of flap transfer is the two-stage reverse sural flap (TS-RSF), in which the pedicle of the flap is exteriorized in the first stage. Flap division and re-inset are done in the second stage. The aim of this paper is to review the flap outcomes and complications among the SS-RSF and TS-RSF reconstruction of soft tissue defects in the distal leg and heel. METHODS: This is a retrospective chart review of RSF being operated in a tertiary care hospital. The duration of study was 1.5 years. Twelve RSFs (6 SS-RSF, 6 TS-RSF) were done for soft tissue defects in the distal leg and heel. Wounds of various etiologies (traumatic, chronic, non-healing ulcers) were reviewed. Trauma was the most common etiology with 8 out of 12 (66.7%) patients. Large wounds, donor site damage and patients with peripheral vascular disease were excluded from the study. RESULTS: Five out of six (83.3%) of TS-RSF healed uneventfully. However, 3 out of 6 (50%) of SS-RSF had partial flap necrosis. All complicated flaps healed well subsequently. No donor site complication was found in any of our patients. CONCLUSION: Pedicle exteriorization in TS-RSF eliminates the element of venous congestion and eventually flaps necrosis. Less technical expertise and minimal morbidity are additional advantages of TS-RSF. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Holistic Care Approach for the Effective Management of Severe Radiation Dermatitis Using Neem (Azadirachta indica) and Honey after Head-and-Neck Radiotherapy.

Head and neck cancer is the eighth common type among all cancer types around the world. Its treatment comprises surgery, radiation therapy, chemotherapy and /or a combination of restoration therapy and social support Conventional fraction size ranges from 1.8 to 3 Grays (Gy) per fraction over 4-6 weeks. The accumulative dose of radiation for the primary treatment of head and neck cancer treatment is 60 to 70 Gy, depending on the irradiation of the tumor. Ionizing Radiotherapy is used along with concurrent chemotherapy which is the standard treatment in locally advanced head and neck cancers. Radiation treatment is commonly delivered in the form of high energy photons through an external beam. These results in ionization of electrons that cause direct strand breaks of cellular DNA and the release of free radicals, resulting in cellular damage to both normal and tumor cells. Radiation disrupts the normal process of wound healing at various stages.

Complement C1r serine protease contributes to kidney fibrosis.

We have previously reported that complement activation precedes the development of kidney fibrosis; however, little is known about the cellular mechanisms involved in this transition. We hypothesized that increased expression of C1 complex protease C1r, the initiator of complement activation, contributes to tubulointerstitial fibrosis and tested this idea in mice with global deletion of C1r. Although expression of C1r in untreated wild-type (WT) mice was higher in the liver compared with kidney tissue, administration of folic acid (FA) led to upregulation of C1r mRNA and protein levels only in kidney tissue. Immunohistochemistry and in situ hybridization experiments localized increased expression of C1r and C1s proteases to renal tubular epithelial cells. C1r-null mice had reduced acute tubular injury and inflammation measured 2 days after FA administration compared with WT mice. C1r deletion reduced expression of C1s, C3 fragment formation, and organ fibrosis measured 14 days after FA administration. Differential gene expression performed in kidney tissue demonstrated that C1r-null mice had reduced expression of genes associated with the acute phase response, complement, proliferation of connective tissue cells (e.g., platelet-derived growth factor receptor-ß), and reduced expression of genes associated with inflammation compared with FA-treated WT mice. In vitro experiments in renal epithelial cells demonstrated that C1s expression is dependent on increased C1r expression and that interferon-γ induces the expression of these two proteases. We conclude that increased expression of C1 complex proteases is associated with increased tissue inflammation and complement C3 formation and represents an important pathogenic mechanism leading to FA-mediated tubulointerstitial fibrosis.

Pericytes and immune cells contribute to complement activation in tubulointerstitial fibrosis.

We have examined the pathogenic role of increased complement expression and activation during kidney fibrosis. Here, we show that PDGFRß-positive pericytes isolated from mice subjected to obstructive or folic acid injury secrete C1q. This was associated with increased production of proinflammatory cytokines, extracellular matrix components, collagens, and increased Wnt3a-mediated activation of Wnt/ß-catenin signaling, which are hallmarks of myofibroblast activation. Real-time PCR, immunoblots, immunohistochemistry, and flow cytometry analysis performed in whole kidney tissue confirmed increased expression of C1q, C1r, and C1s as well as complement activation, which is measured as increased synthesis of C3 fragments predominantly in the interstitial compartment. Flow studies localized increased C1q expression to PDGFRß-positive pericytes as well as to CD45-positive cells. Although deletion of C1qA did not prevent kidney fibrosis, global deletion of C3 reduced macrophage infiltration, reduced synthesis of C3 fragments, and reduced fibrosis. Clodronate mediated depletion of CD11bF4/80 high macrophages in UUO mice also reduced complement gene expression and reduced fibrosis. Our studies demonstrate local synthesis of complement by both PDGFRß-positive pericytes and CD45-positive cells in kidney fibrosis. Inhibition of complement activation represents a novel therapeutic target to ameliorate fibrosis and progression of chronic kidney disease.

Macrophage depletion ameliorates nephritis induced by pathogenic antibodies.

Kidney involvement affects 40-60% of patients with lupus, and is responsible for significant morbidity and mortality. Using depletion approaches, several studies have suggested that macrophages may play a key role in the pathogenesis of lupus nephritis. However, "off target" effects of macrophage depletion, such as altered hematopoiesis or enhanced autoantibody production, impeded the determination of a conclusive relationship. In this study, we investigated the role of macrophages in mice receiving rabbit anti-glomerular antibodies, or nephrotoxic serum (NTS), an experimental model which closely mimics the immune complex mediated disease seen in murine and human lupus nephritis. GW2580, a selective inhibitor of the colony stimulating factor-1 (CSF-1) receptor kinase, was used for macrophage depletion. We found that GW2580-treated, NTS challenged mice did not develop the increased levels of proteinuria, serum creatinine, and BUN seen in control-treated, NTS challenged mice. NTS challenged mice exhibited significantly increased kidney expression of inflammatory cytokines including RANTES, IP-10, VCAM-1 and iNOS, whereas GW2580-treated mice were protected from the robust expression of these inflammatory cytokines that are associated with lupus nephritis. Quantification of macrophage related gene expression, flow cytometry analysis of kidney single cell suspensions, and immunofluorescence staining confirmed the depletion of macrophages in GW2580-treated mice, specifically within renal glomeruli. Our results strongly implicate a specific and necessary role for macrophages in the development of immune glomerulonephritis mediated by pathogenic antibodies, and support the development of macrophage targeting approaches for the treatment of lupus nephritis.

The Yaa locus and IFN-α fine-tune germinal center B cell selection in murine systemic lupus erythematosus.

Male NZW/BXSB.Yaa (W/B) mice express two copies of TLR7 and develop pathogenic autoantibodies, whereas females with only one copy of TLR7 have attenuated disease. Our goal was to analyze the regulation of the autoantibody response in male and female W/B mice bearing the autoreactive site-directed H chain transgene 3H9. Serum anti-dsDNA Abs appeared in males at 12 wk, and most had high-titer IgG anti-dsDNA and anti-cardiolipin Abs and developed >300 mg/dl proteinuria by 8 mo. Females had only low-titer IgG anti-cardiolipin Abs, and none developed proteinuria by 1 y. Males had a smaller marginal zone than females with a repertoire that was distinct from the follicular repertoire, indicating that the loss of marginal zone B cells was not due to diversion to the follicular compartment. Vk5-43 and Vk5-48, which were rare in the naive repertoire, were markedly overrepresented in the germinal center repertoire of both males and females, but the VJ junctions differed between males and females with higher-affinity autoreactive B cells being selected into the germinal centers of males. Administration of IFN-α to females induced anti-cardiolipin and anti-DNA autoantibodies and proteinuria and was associated with a male pattern of junctional diversity in Vk5-43 and Vk5-48. Our studies are consistent with the hypothesis that presence of the Yaa locus, which includes an extra copy of Tlr7, or administration of exogenous IFN-α relaxes the stringency for selection in the germinal centers resulting in increased autoreactivity of the Ag-driven B cell repertoire.

The multiple chemokine-binding bovine herpesvirus 1 glycoprotein G (BHV1gG) inhibits polymorphonuclear cell but not monocyte migration into inflammatory sites.

Chemokines facilitate the recruitment of inflammatory cells into tissues, contributing to target organ injury in a wide range of inflammatory and autoimmune diseases. Targeting either single chemokines or chemokine receptors alters the progression of disease in animal models of rheumatoid arthritis and lupus with varying degrees of efficacy but clinical trials in humans have been less successful. Given the redundancy of chemokine-chemokine receptor interactions, targeting of more than one chemokine may be required to inhibit active inflammatory disease. To test the effects of multiple-chemokine blockade in inflammation, we generated an adenovirus expressing bovine herpesvirus 1 glycoprotein G (BHV1gG), a viral chemokine antagonist that binds to a wide spectrum of murine and human chemokines, fused to the Fc portion of murine IgG2a. Administration of the adenovirus significantly inhibited thioglycollate-induced migration of polymorphonuclear leukocytes into the peritoneal cavity of BALB/c mice and reduced both clinical severity and articular damage in K/BxN serum transfer-induced arthritis. However, treatment with BHV1gG-Ig fusion protein did not prevent monocyte infiltration into the peritoneum in the thioglycollate model and did not prevent renal monocyte infiltration or nephritis in lupus-prone NZB/W mice. These observations suggest that the simultaneous inhibition of multiple chemokines by BHV1gG has the potential to interfere with acute inflammatory responses mediated by polymorphonuclear leukocytes, but is less effective in chronic inflammatory disease mediated by macrophages.

Anti-tumor necrosis factor α treatment of interferon-α-induced murine lupus nephritis reduces the renal macrophage response but does not alter glomerular immune complex formation.

OBJECTIVE: To analyze the mechanism for the therapeutic effects of tumor necrosis factor α (TNFα) inhibition in a murine model of systemic lupus erythematosus. METHODS: We used the (NZB × NZW)F(1) (NZB/NZW) mouse model of interferon-α-induced lupus nephritis and treated mice with TNF receptor type II (TNFRII) Ig after TNFα expression was detected in the kidneys. Autoantibodies were measured by enzyme-linked immunosorbent assay (ELISA), and autoantibody- forming cells were determined using an enzyme-linked immunospot assay. Activation of splenocytes was analyzed by flow cytometry. Kidneys were harvested and analyzed using flow cytometry, immunohistochemistry, ELISA, Western blotting, and real-time polymerase chain reaction. RESULTS: TNFRII Ig treatment stabilized nephritis and markedly prolonged survival. Autoantibody production and systemic immune activation were not inhibited, but the renal response to glomerular immune complex deposition was attenuated. This was associated with decreases in renal production of chemokines, renal endothelial cell activation, interstitial F4/80(high) macrophage accumulation, tubular damage, and oxidative stress. In contrast, perivascular lymphoid aggregates containing B cells, T cells, and dendritic cells accumulated unabated. CONCLUSION: Our data suggest that TNFα is a critical cytokine that amplifies the response of the nephron to immune complex deposition, but that it has less influence on the response of the systemic vasculature to inflammation.

BAFF/APRIL inhibition decreases selection of naive but not antigen-induced autoreactive B cells in murine systemic lupus erythematosus.

BAFF inhibition is a new B cell-directed therapeutic strategy for autoimmune disease. Our purpose was to analyze the effect of BAFF/APRIL availability on the naive and Ag-activated B cell repertoires in systemic lupus erythematosus, using the autoreactive germline D42 H chain (glD42H) site-directed transgenic NZB/W mouse. In this article, we show that the naive Vκ repertoire in both young and diseased glD42H NZB/W mice is dominated by five L chains that confer no or low-affinity polyreactivity. In contrast, glD42H B cells expressing L chains that confer high-affinity autoreactivity are mostly deleted before the mature B cell stage, but are positively selected and expanded in the germinal centers (GCs) as the mice age. Of these, the most abundant is VκRF (Vκ16-104*01), which is expressed by almost all IgG anti-DNA hybridomas derived from the glD42H mouse. Competition with nonautoreactive B cells or BAFF/APRIL inhibition significantly inhibited selection of glD42H B cells at the late transitional stage, with only subtle effects on the glD42H-associated L chain repertoire. However, glD42H/VκRF-encoded B cells were still vastly overrepresented in the GC, and serum IgG anti-DNA Abs arose with only a slight delay. Thus, although BAFF/APRIL inhibition increases the stringency of negative selection of the naive autoreactive B cell repertoire in NZB/W mice, it does not correct the major breach in B cell tolerance that occurs at the GC checkpoint.

A unique hybrid renal mononuclear phagocyte activation phenotype in murine systemic lupus erythematosus nephritis.

Renal infiltration with mononuclear cells is associated with poor prognosis in systemic lupus erythematosus. A renal macrophage/dendritic cell signature is associated with the onset of nephritis in NZB/W mice, and immune-modulating therapies can reverse this signature and the associated renal damage despite ongoing immune complex deposition. In nephritic NZB/W mice, renal F4/80(hi)/CD11c(int) macrophages are located throughout the interstitium, whereas F4/80(lo)/CD11c(hi) dendritic cells accumulate in perivascular lymphoid aggregates. We show here that F4/80(hi)/CD11c(int) renal macrophages have a Gr1(lo)/Ly6C(lo)/VLA4(lo)/MHCII(hi)/CD43(lo)/CD62L(lo) phenotype different from that described for inflammatory macrophages. At nephritis onset, F4/80(hi)/CD11c(int) cells upregulate cell surface CD11b, acquire cathepsin and matrix metalloproteinase activity, and accumulate large numbers of autophagocytic vacuoles; these changes reverse after the induction of remission. Latex bead labeling of peripheral blood Gr1(lo) monocytes indicates that these are the source of F4/80(hi)/CD11c(int) macrophages. CD11c(hi)/MHCII(lo) dendritic cells are found in the kidneys only after proteinuria onset, turnover rapidly, and disappear rapidly after remission induction. Gene expression profiling of the F4/80(hi)/CD11c(int) population displays increased expression of proinflammatory, regulatory, and tissue repair/degradation-associated genes at nephritis onset that reverses with remission induction. Our findings suggest that mononuclear phagocytes with an aberrant activation profile contribute to tissue damage in lupus nephritis by mediating both local inflammation and excessive tissue remodeling.