IntroductionCrohn’s disease (CD) is a disabling inflammatory disorder with highly variable response to biologic therapies. Despite the availability of multiple biologic agents, a significant proportion of patients experience primary non-response, while others initially respond but subsequently develop secondary loss of response, leading to sequential treatment failures and increased healthcare burden. The disease course and response to treatment are remarkably heterogeneous among patients, and a better understanding of the personalised pathways affected is required. Identifying early biomarkers of treatment efficacy is crucial for improving patient outcomes and reducing unnecessary healthcare costs.MethodsIn this study, we comprehensively analysed T cell subpopulations in blood and lamina propria, together with serum cytokine profiles, in CD patients receiving the IL-12/IL-23 inhibitor ustekinumab.ResultsThe most remarkable findings were observed in peripheral blood. At week 24, good responders showed decreased Th1, increased Th2, and reduced IL-17A serum levels compared with non-responders. Importantly, elevated IL-12/IL-23 serum levels at week 8 associated with favourable clinical and endoscopic outcomes, suggesting effective pathway blockade.DiscussionThese findings support the measurement of serum IL-12/IL-23 at week 8 as a simple, early predictor of ustekinumab response in CD, potentially guiding personalised treatment strategies and ultimately long-term response.

IntroductionThe first wave of Coronavirus disease 2019 (COVID-19), driven by the global emergence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), severely affected Spain with high infection and mortality rates across the country. Although numerous common and rare genetic variants affecting immune-related pathways have been associated with susceptibility to infection and severe disease, the contribution of complement system remains comparatively understudied.MethodsIn this work, we analyzed the frequencies and severity associations of complotype-related common polymorphisms and rare complement variants in whole-exome sequencing data from a Spanish cohort accounting for 154 adults hospitalized due to severe COVID-19.ResultsOur results indicate that the CFHR4 rs7417769 (p.N209S) and CFH rs1061170 (p. Y402H) common polymorphisms are significantly associated with protection against acute respiratory distress syndrome (ARDS), while the C3 rs2230199 (p.R102G) and MASP2 rs7255087 (p.D120G) polymorphisms respectively correlated with low and high C3 levels. The marked over-representation of the C1R rs117402032 and C8A rs143523574 polymorphisms and increased frequency of heterozygous carriers of alleles previously associated with low FCN2 and FCN3 levels, suggest a link beween defective complement activation and increased rates of SARS-CoV-2 infection and support a pivotal role for the lectin pathway in the pathogenesis of COVID-19.DiscussionTogether, these results demonstrate that common variants in complement genes modulate susceptibility to severe COVID-19 and its clinical complications. They also identify promising, testable genetic biomarkers with potential utility not only for SARS-CoV-2, but also for preparedness against future emerging infectious threats.

Factor H (FH) is the main regulator of the complement alternative pathway, and it is essential to prevent complement-mediated autologous damage. Many pathogens express FH-binding proteins on their surface that recruit human FH as a strategy to avoid or limit their elimination by the host complement. The FH-Related Proteins (FHR-1, FHR-2, FHR-3, FHR-4A, and FHR-5) share sequential and structural homology with FH that result from their common ancestry, but none of them can regulate complement like FH. While the precise contribution of FHRs in human complement is still not completely understood, it has been proposed that these proteins have been conserved along evolution because they outcompete FH binding to the microbial surfaces, thus allowing pathogen elimination. In this review, we recapitulate the current evidence of the interaction between FHRs and pathogens. We describe the results from “in vitro” studies with microbial isolates and purified proteins, and the few studies that have addressed the quantification of FH and FHRs in patients during infection. We also provide an analysis comparing the frequency of common genetic variants, including ΔCFHR3-CFHR1, in different geographical regions, and the incidence of Invasive Meningococcal Disease. All the data are discussed in the context of the role of FHRs as FH-deregulators, and at the light of recent findings supporting a function as complement activators.

Generalized lipodystrophy is a rare syndrome of diffuse adipose tissue loss that may associate with metabolic and/or autoimmune comorbidities. The role of perilipin (PLIN1—a protein almost exclusively found in adipocytes) in lipodystrophy was first suggested in 2011 by the identification of deleterious genetic variants in PLIN1 in familial forms of lipodystrophy.1 More recently, the presence of autoantibodies against PLIN1 has been evidenced by Corvillo et al. in patients with acquired generalized lipodystrophy (AGL).2 Subsequently, two cohorts of patients with AGL were studied, and autoantibodies against PLIN1 were found in 37% and 50%, respectively,3, 4 especially in patients with associated autoimmune diseases. An underlying inborn error of immunity has been reported in one patient (APECED syndrome—autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy).4 In vitro evidence suggests that anti-PLIN1 autoantibodies play a pathogenic role rather than being an epiphenomenon. The proposed pathological effect of anti-PLIN1 autoantibodies is to block the interaction between PLIN1 and αβ-hydrolase domain containing 5 (ABHD5), causing ABDH5 to translocate to the cytosol, thereby increasing lipolysis.3, 5 While these exciting mechanistic and prevalence data are emerging, detailed clinical description of anti-PLIN1-positive patients are scarce in the literature. Here, we report the clinical presentation and disease course of two pediatric patients with common autoimmune diseases (type 1 diabetes, autoimmune hepatitis) who developed AGL in the presence of anti-PLIN1 antibodies. Patient 1 is a girl who presented at the age of 3 years with established features of generalized lipodystrophy (without prior or associated panniculitis): subcutaneous fat loss, muscular appearance for age, and phlebomegaly (Figure 1A). She also had vitiligo, acanthosis nigricans, and a cushingoid face. Personal and family history was unremarkable. Laboratory studies revealed elevated liver enzymes, hypergammaglobulinemia, negative serology tests for autoimmune hepatitis, normal C3, and slightly decreased C4 (0.13 g/L, reference range 0.16–0.38 g/L). Liver biopsy was consistent with autoimmune hepatitis (lymphocytic and plasma cells infiltration). She was treated with steroids and mycophenolate mofetil. After a first relapse, she was switched to azathioprine. Several hepatitis flares, possibly caused by poor adherence, occurred over the next 10 years and were managed with steroids and azathioprine dosage increase (Figure S1). Pronounced hypergammaglobulinemia also persisted. At 14.5 years of age, another liver biopsy harvested during hepatitis flare showed persistent hepatitis, with an elevated number of IgG4+ cells (Figure S1). Azathioprine was discontinued for rituximab, resulting in the current state of remission after 1.5 years on this therapy. The features of lipodystrophy have remained unchanged, without evolution throughout the disease course. Additional investigations on serum taken before receiving rituximab revealed positive anti-PLIN1 IgG and IgM antibodies by ELISA, which were further confirmed by indirect immunofluorescence (Hospital La Paz Institute for Health Research Madrid) (Figure 1B and Figure S2).3 A trio whole-exome sequencing did not reveal any pathogenic variant in genes known to cause inborn errors of immunity or inherited lipodystrophy (Table S1). Patient 2 is a boy who was diagnosed with type 1 diabetes at the age of 1.5 years without relevant personal or family history. Three months later, his parents reported diffuse loss of subcutaneous fat with sparing of the face (Figure 2A), despite acceptable glycemic control with a subcutaneous insulin pump. There was no clinical evidence of panniculitis. Laboratory tests showed undetectable leptin concentration (<1.6 μg/L, reference range: 2.2–11.1) and C-peptide (<0.01 nmol/L), normal C3/C4, negative autoantibodies against insulin, IA2A, GADA, and positive anti-PLIN1 IgG antibodies by ELISA, which were further confirmed by indirect immunofluorescence (Hospital La Paz Institute for Health Research, Madrid) (Figure 2B and Figure S2).3 A serum sample taken and stored at diabetes diagnosis was tested and also revealed the presence of anti-PLIN1 IgG antibodies, with similar titers (Figure 2B and Figure S2). Liver enzymes remained slightly elevated (ALT: 67–218 U/L, reference value <41) during 1 year and normalized spontaneously. Sequencing of a panel of genes involved in inherited lipodystrophy did not detect any pathogenic variant (Table S1). At the age of 3.5 years, the patient had a stable evolution with persistent generalized lipodystrophy. AGL with anti-PLIN1 antibodies has been reported to be associated with one or more autoimmune diseases in 82%–85% of cases, autoimmune hepatitis being the most frequent.3, 4 Our report illustrates that AGL may be the presenting symptom or occur later in the disease course in a patient with known autoimmunity. Noteworthy, the autoantibody isotypes detected in our patients do not correlate with the clinical onset of AGL, a finding similar to previous studies.3 Longitudinal studies are needed to ascertain whether there is a transition from IgM to IgG during the course of the disease or, conversely, whether these two classes persistently coexist in some patients. In addition, we provide the first evidence that anti-PLIN1 antibodies are already present before onset of clinically apparent AGL, paving the way for screening and potential preventive interventions in presymptomatic patients with positive autoantibodies. If confirmed on additional patients, this observation might also represent an advance in the understanding of the role of anti-PLIN1 antibodies. Indeed, some authors have raised the possibility that these autoantibodies could be a consequence of adipose tissue damage (rather than its cause) and appear secondarily to exposition of tissue-restricted antigens.5 Our report would argue against the latter hypothesis, although we cannot exclude that subclinical adipose tissue loss was already present when the first sample was tested. Overall, an in vivo study of the consequences of anti-PLIN1 antibodies remains necessary for a clear assessment of their potential pathogenic role. In conclusion, physicians caring for patients with autoimmune diseases should be aware of this rare entity, to ensure prompt diagnosis, appropriate patient information, and monitoring of comorbidities. Clément Triaille: Conceptualization; investigation; writing – original draft; visualization. Fernando Corvillo: Investigation; writing – review and editing; data curation; formal analysis. Ann Mertens: Writing – review and editing. Ilse Hoffman: Writing – review and editing; data curation; investigation. Tania Roskams: Investigation; writing – review and editing. Margarita López-Trascasa: Investigation; writing – review and editing; data curation. Lien De Somer: Investigation; writing – review and editing; data curation. Kristina Casteels: Investigation; writing – review and editing; data curation. We are grateful to the patients and their family for participating in this study. We thank the Belgian Diabetes Registry for providing the serum sample of patient 2. CT is partly funded by WBI World (Bourses d'excellence, Wallonie-Bruxelles International), Fondation CHU Sainte-Justine, and Fondation médicale Horlait-Dapsens. FC was awarded a research fellowship by the Asociación Española de Familiares y Afectados de Lipodistrofias (AELIP). The authors have no competing interest to disclose in relationship with the present manuscript. This study was approved by the ethics committee of UZ/KU Leuven (reference: S69540). Samples were obtained from the patients with written informed consent. Patients and/or legal representative provided written informed consent for publication of case report and clinical photographs. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/pai.70026. Access to additional information can be discussed on an ad hoc basis following contact with the corresponding author. Figure S1. Figure S2. Table S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

El sistema del complemento es un entramado bioquímico de proteínas solubles y de membrana implicadas en la respuesta inmune innata. El complemento es esencial para la homeostasis y la defensa frente a patógenos, pero un desequilibrio entre sus procesos de activación y regulación puede causar daño tisular. Un ejemplo relevante es el síndrome hemolítico-urémico atípico (SHUa), que a menudo se asocia con una función anómala del regulador del complemento Factor H (FH). El complemento interacciona con los sistemas de la coagulación, fibrinólisis, renina-angiotensina y calicreína-cinina (SCC). El SCC es una cascada proinflamatoria y procoagulante que se puede activar conformacionalmente o mediante proteólisis, y que incluye a la proteasa precalicreína, a los factores de coagulación FXI y FXII, y al sustrato/cofactor cininógeno de alto peso molecular. «In vitro», el SCC desencadena una serie de interacciones entre FXI, FXII, FH y otras proteínas que provocan la activación directa o indirecta del complemento. Esta capacidad del SCC para activar el complemento afectaría a la coagulación y a la respuesta inmunológica del organismo, pero nunca se han explorado sus posibles consecuencias «in vivo». Esta revisión sintetiza las principales características fisiopatológicas del SCC en el contexto del daño renal mediado por el complemento, en particular en el SHUa.

Rheumatoid arthritis (RA) and axial spondyloarthritis (axSpA) are the most common rheumatic diseases (RDs). They are characterised by chronic inflammation of the joints and musculoskeletal components. Adipose tissue releases adipokines that regulate numerous biological processes, including inflammation, thus stabilising the relationship between RDs and adipokines, such as adiponectin and leptin. The correlation between these adipokines and RA highlights a possible role of other adipokines in RDs. Therefore, we decided to analyse the role of the adipokine adipsin in the context of RDs. Adipsin levels were measured in serum from 233 patients (66 early-RA, 98 established-RA, and 69 axSpA) and 88 healthy controls (HCs). Associations between adipsin and clinical or demographic variables were assessed using univariate and multivariate regression models. The diagnostic utility of adipsin was evaluated using ROC curve analysis. Our study revealed that adipsin concentrations were significantly higher in both early-RA and established-RA patients than in axSpa and in HCs. No significant differences were found between axSpA and HCs. In early-RA, female sex and prednisone use were independently associated with higher adipsin levels. In established-RA, age and disease duration showed a positive association with adipsin concentrations. In axSpA, disease duration and CRP correlated with adipsin levels, but no consistent associations were observed for BMI or HLA-B27 status. ROC analysis revealed good discriminatory capacity of adipsin to differentiate early-RA from HCs (AUC = 0.82; optimal cut-off: 1.325 µg/mL). We provide evidence supporting the involvement of adipsin in the pathophysiology of RA and highlight its value as a new potential biomarker.

The complement system is a network of soluble and cell surface proteins primarily involved in innate immune responses. Complement signaling is essential for pathogen defence and homeostasis, but an activation-regulation imbalance can lead to tissue damage. This phenomenon has been implicated in kidney diseases such as atypical Haemolytic Uraemic Syndrome (aHUS), frequently associated with dysfunction of the complement regulator Factor H (FH). Physiologically, complement interacts with the coagulation, fibrinolysis, renin-angiotensin and kallikrein-kinin systems (KKS). The KKS is a proinflammatory and procoagulant cascade comprised of the protease prekallikrein, the coagulation factors XI (FXI) and XII (FXII), and the cofactor/substrate high-molecular-weight kininogen. KKS can be activated conformationally or proteolytically. KKS activation in vitro triggers a number of biochemical interactions between FXI, FXII, FH and other complement proteins that result in direct or secondary complement activation. These functional links point to an overall complement pro-activating role for the KKS that has implications for coagulation and immunity, but whose physiological consequences in vivo remain largely unexplored. This review aims to summarize the main physiopathological events of KKS activation in the context of complement-mediated kidney disease, with particular emphasis in aHUS.

The activation of the complement alternative pathway (AP) is involved in the pathogenesis of IgA nephropathy (IgAN). AP is regulated by the plasma glycoprotein Factor H (FH), whose function can be affected by its homologous proteins FHRs. Elevated plasma levels of 2 of these proteins, FHR-1 and FHR-5, have been described in IgAN patients, and are associated with renal progression. Our aim is to analyze the contribution of these proteins, as well as FHR-2 and FHR-4A, in a new cohort of IgAN patients, and to explore their prognostic role in renal progression. We conducted a prospective observational study in 67 patients with a histologically confirmed diagnosis of IgAN (23 renal transplants with baseline IgAN) and 79 healthy controls. Absolute plasma levels of FH, FHR-1, FHR-2, FHR-4A and FHR-5 were determined by ELISA assays and subsequently normalized to a reference value obtained from a healthy subject. The protein expression profiles thus obtained were analyzed by unsupervised hierarchical clustering (HeatMap) to identify control and patient-associated profiles. Renal progression was defined as reaching CKD stage 5 or loss >40% of eGFR The mean age of the patients was 49 ± 15 years, with a follow-up of 84 months (IQR 56–103), eGFR of 63 ± 23 ml/min/1.73 m2 and uPCR 330 mg/g (IQR 110–640). Absolute levels of FH, FHR-1, FHR2 and FHR4-A were significantly higher in patients than in the control group, and patients with IgAN in the native kidney and in the functioning kidney transplant behaved in the same way. These data suggest that elevated levels of these proteins are mostly determined genetically, and to a lesser stent by disease activity. Two relevant expression profiles were identified. In PROFILE 1, the levels of FH, FHR-1, FHR-2 and FHR-4A are higher than in the reference sample, and in PROFILE 2 these levels are lower. PROFILE 1 was only found in 16 patients, 62 % of whom had renal progression (eGFR 44 vs 81 ml/min P < 0.001 and proteinuria 395 vs 189 mg/g p: 0.03), with an OR risk for renal progression (OR 4.6, 95% CI 1.4–15, p: 0.011). In PROFILE 2, controls predominate (n = 8/9), suggesting that this is protective for disease development OR 0.11 (95% CI 0.014–0.9, p: 0.04). Plasma expression profiles of FH and FHRs proteins are probably more informative for estimating the risk of renal progression than the absolute levels of these proteins. In the future, these different protein expression profiles could guide better treatment decisions.

Severe infectious diseases remain the leading cause of death in children and young adults worldwide. Monogenic inborn errors of immunity (IEIs) are traditionally defined as a heterogeneous group of rare inborn genetic diseases affecting the functioning of the immune system. Greater awareness has led to the clinical definition of 485 monogenic IEIs and whole exome sequencing (WES) is becoming increasingly relevant for IEI genetic diagnosis. The current protocol for IEI genetic studies includes manual filtering of the list of genes obtained as a WES read-out providing a short list of candidate genes. This procedure is time-consuming and can produce mistakes due to human error in manual filtering. IEIVariantFilter is a new web-based bioinformatics tool to speed up and refine the genetic diagnosis of IEI patients oriented for users in the biomedical field without needing bioinformatics expertise. IEIVariantFilter prioritizes genetic variants based on ranges of zygosity, the quality of reads, the predicted variant effect, and genes related to immunity, considering a consanguineous hypothesis whenever necessary. IEIVariantFilter facilitates gene and variant list prioritization, speeding up the identification of candidate disease-causing variants for validation by experimental studies. The software improves the genetic diagnosis of patients, thereby facilitating precision medicine and fast and proper treatment.

Background Barraquer-Simons syndrome (BSS) is a rare, acquired form of lipodystrophy characterized by progressive loss of upper body subcutaneous fat, which affects face, upper limbs, and trunk. The pathogenesis of the disease is not entirely known and may involve autoimmune mechanisms.Aim This study aimed to provide a comprehensive picture of the clinical, immunological, and metabolic features of a large cohort of patients with BSS. Our primary objectives included the validation of existing diagnostic tools, the evaluation of novel diagnostic approaches, and the exploration of potential disease triggers or genetic predispositions.Subjects and Methods Twenty-six patients were diagnosed with BSS based on accepted criteria defined by international guidelines. Anthropometric parameters, biochemical tests, organ- and non-organ-specific autoantibodies, HLA status, and screening of the LMNB2 gene were performed.Results Patients were predominantly females (73%); fat loss occurred mostly during childhood (77%) at a median age of 8 years. Among various anthropometric measures, the ratio between the proportion of fat mass in upper limbs and lower limbs showed the best predictive value for diagnosis. A total of 11.5% of patients had diabetes, 34.6% dyslipidemia, and 26.9% hepatic steatosis. Seventy-five percent of children and 50% of adults had C3 hypocomplementemia; 76% of patients were positive for 1 or more autoantibodies. HLA-DRB1 11:03 had higher allelic frequencies compared with the general population. A single variant in the LMNB2 gene was found in 1 patient.Conclusion BSS has a childhood onset and is often associated with autoimmune diseases. Skinfold thickness measurements and fat assessment by dual energy X-ray absorptiometry are useful tools to identify the disease. C3 hypocomplementemia and the presence of autoantibodies may be used as additional diagnostic supportive criteria but the prevalence of C3 hypocomplementemia may be lower than previously reported.

Human BCL10 deficiency causes combined immunodeficiency with bone marrow transplantation as its only curative option. To date, there are four homozygous mutations described in the literature that were identified in four unrelated patients. Here, we describe a fifth patient with a novel mutation and summarize what we have learned about BCL10 deficiency. Due to the severity of the disease, accurate knowledge of its clinical and immunological characteristics is instrumental for early diagnosis and adequate clinical management of the patients.

Abstract Background and Aims Complement Factor H (FH) function is modulated by their homologous FH related proteins (FHRs), which compete with FH for binding to certain ligands on plasma and on cellular surfaces. Genetic variants in the CFH-CFHRs region (coding for FH and the FHRs) confer susceptibility or protection to complement-mediated renal diseases, such as IgA nephropathy (IgAN). The CFHR3-CFHR1 deletion provides a strong protection against IgAN, while protein levels of FHR-1 and FHR-5 are higher in plasma samples from IgAN patients than in controls. The contribution of other FHR proteins to IgAN is so far unknown. The objective of this study is to determine the role of FH and FHR proteins in the renal progression of IgAN, and to establish whether plasma levels of these proteins could at least partially explain the heterogeneity observed in the patients. Method Plasma levels of FH, FHR-1, FHR-2, FHR-4A and FHR-5 was carried out in patients diagnosed with IgAN by renal biopsy (n = 45), and compared with a control group (n = 45). Protein levels observed in the IgAN patients were subsequently compared according to renal progression. Results Forty-five IgAN patients with a mean age of 46±18 years and 71% male were included. 15% of patients were hypertensive and 4% were diabetic. 90% had antiproteinuric treatment, and 44% immunosuppressive treatment. In renal biopsy according to Oxford classification: M1: 11,4%, E1:8,8%, S1:22%; T1:10,5%. The basal creatinine was 1.3 ± 0.47mg/dl (eFG 67; IQR 16-116 ml/min/1.73m2), and proteinuria (uPCR) 500 mg/g (IQR 30-3220). The patients were followed for a median of 83 months (IQR 0-111 months). Seven patients progressed, defined as a loss of >40% of glomerular filtration rate (GFR). FH and FHR-1 plasma levels were significantly higher in IgAN cases (FH: cases 2400±650 nM vs controls 1980±573 nM, p = 0.002), (FHR-1: cases 497±256 vs controls 379±152 nM; p = 0.011), but the patients had a lowest FH/FHR-1 ratio (FH/FHR-1 cases 5.4±2.58 vs controls 6.3±3.67, p = 0.061). The levels of FHR-2 and FHR-4A were also elevated in IgAN cases (FHR-2: cases 214±127 vs controls 132±71 nM, p<0.0001), (FHR-4A: cases 45±22 vs controls 31±14 nM, p<0.001), while no differences in FHR-5 levels were found (FHR-5: cases 25.7 ± 17 vs controls 27 ± 15, p = 0.7). When the patients who progressed and those who did not progressed were compared, it was observed that, as previously described, FHR-1 levels showed a tendency to be higher in progressing patients (566±333 vs 451±203 nM, p = 0.2), and a lower FH/FHR-1 ratio (4.1±2.4 vs 5.8±2.6, p = 0.1). Moreover, we also observed a similar trend in the other FHR proteins: (FHR-2: 304±106 vs 195 ±118 nM, p = 0.043); (FHR-4A: 53±26 vs 43±21, p = 0.29); (FHR-5: 41±35 vs 23±8.9 nM, p = 0.2). Conclusion We observed increased levels of several FHR proteins and FHRs/FH ratios in our IgAN cohort. We confirm that FHR-1 is implicated in renal progression, and we also show that other proteins of the family (FHR-2, FHR-4, and FHR-5) also contribute, suggesting that dysregulation of the alternative Complement pathway by FHR proteins is involved in IgAN. Genetic studies in the CFH-CFHR region may provide additional evidence to our protein findings.

Complement overactivation has been reported in most patients with Barraquer–Simons syndrome (BSS), a rare form of acquired partial lipodystrophy. Complement Factor D (FD) is a serine protease with a crucial role in the activation of the alternative pathway of the complement system, which is mainly synthesized by adipose tissue. However, its role in the pathogenesis of BSS has not been addressed. In this study, plasma FD concentration was measured in 13 patients with BSS, 20 patients with acquired generalized lipodystrophy, 22 patients with C3 glomerulopathy (C3G), and 50 healthy controls. Gene expression and immunohistochemistry studies were assayed using atrophied adipose tissue from a patient with BSS. We found significantly elevated FD levels in BSS cases compared with the remaining cohorts (p < 0.001). There were no significant differences in FD levels between sexes but FD was strongly and directly associated with age in BSS (r = 0.7593, p = 0.0036). A positive correlation between FD and C3 was seen in patients with C3G, characterized by decreased FD levels due to chronic C3 consumption, but no correlation was detected for BSS. Following mRNA quantification in the patient’s adipose tissue, we observed decreased CFD and C3 but elevated C5 transcript levels. In contrast, the increased FD staining detected in the atrophied areas reflects the effects of persistent tissue damage on the adipose tissue, thus providing information on the ongoing pathogenic process. Our results suggest that FD could be a reliable diagnostic biomarker involved in the pathophysiology of BSS by promoting unrestrained local complement system activation in the adipose tissue environment.

BackgroundHereditary angioedema due to the Thr328Lys variant in the coagulation factor XII (HAE-FXII) affects mainly women in whom the symptomatology is dependent on high estrogen levels. Clinical variability and incomplete penetrance are challenging features that hinder the diagnosis and management of HAE-FXII. The c.-4T>C Kozak polymorphism is the only common variation accounting for FXII plasma levels and was previously shown to modify the course of HAE due to C1-Inhibitor deficiency.ObjectivesTo assess the influence of the c.-4T>C polymorphism on disease expression in 39 Spanish HAE-FXII index patients.MethodsThe c.-4T>C polymorphism was sequenced by the standard Sanger method, and HAE severity was calculated according to the score by Cumming et al. (2003) The activation of the contact system was quantified by the kallikrein-like activity of plasma in chromogenic assays upon activation with high-molecular-weight dextran sulfate.ResultsThe c.-4CC genotype was overrepresented in the studied cohort: 82% were CC-homozygous (expected frequency = 59%) and 18% were CT-heterozygous (expected frequency = 39%) (p = 0.001). Patients with a c.-4CC genotype exhibited higher kallikrein-like activity (0.9659 ± 0.1136) than those with a c.-4TC genotype (0.7645 ± 0.1235) (p = 0.024) or healthy donors. Moreover, the polymorphism influenced HAE-FXII severity score (c.-4CC = 4.43 ± 2.28 vs c.-4TC = 2.0 ± 1.15; p = 0.006) but not the degree of estrogen dependence or time until remission.ConclusionThe c.-4T>C polymorphism is overrepresented in a Spanish HAE-FXII cohort and significantly influences the degree of contact system activation and the clinical severity of the disease.

Barraquer–Simons syndrome (BSS), a form of acquired partial lipodystrophy, is a rare condition characterized by gradual loss of adipose tissue from the upper body, keeping intact the white adipose tissue of the lower extremities. The etiology of BSS is not well understood, and clinical follow‐up studies have not been assessed in these patients. Moreover, no histological studies have been conducted during the active phase of the disease, and complement system activation products have not been sought in the affected areas. The objective of this work was to analyze the clinical, immunological and histological events in an 11‐year‐old girl with BSS over a 5‐year follow‐up period. Clinical data were collected during six regular visits for a time period of 5 years. The circulating levels of C3, C3adesArg (a product released upon C3 activation), C4 and immunoglobulins (Ig) were quantified in serum while fat tissue from lipoatrophic areas was examined by immunohistochemical and immunofluorescence approaches. In her regular visits, no clinical or laboratory abnormalities had been observed in the patient, except for the progression of lipoatrophy linked to the C3 hypocomplementemia and the occurrence of C3 nephritic factor. Adipose tissue from the patient showed atrophied and dead adipocytes, an abnormal production of extracellular matrix, and a remarkable accumulation of infiltrating CD68 macrophages and adipocyte precursors (marked by c‐Kit positiveness). Simultaneous detection of IgG, C3, C5a and C5b‐9 proved the ongoing complement activity and complement‐directed injury within the adipose tissue. Our results showed the first evidence that the complement system hyperactivation occurs within the adipose tissue and is linked with fat loss in patients with BSS.

Following the publication of the original article [1], the authors have requested to amend the Abstract and Discussion section as follows.