Hypocomplementemia Research Articles

C3 glomerulonephritis with genetically confirmed C3 deficiency in a pediatric patient: a case report

Complement component 3 glomerulonephritis (C3GN) is a rare kidney disease characterized by complement dysregulation that results in prominent complement component 3 (C3) deposition in the kidneys. The clinical course of C3GN varies from mild hematuria to progressive chronic kidney disease. In most patients, C3GN is driven by acquired factors, namely, autoantibodies that target C3 or C5 convertases. Genetic variations in complement-related genes are less frequent. We report the case of a 9-yearold Korean boy who presented with microscopic hematuria and a persistently low C3 level and had biopsy findings of C3GN, with the presence of a C3 gene mutation: a frameshift mutation associated with C3 deficiency. However, the patient did not exhibit any other symptoms of complement deficiency. Direct DNA sequencing of his family members revealed the same genetic mutation in his father and older brother. This case report is significant because there are very few such reports worldwide concerning gene mutations related to C3 deficiency to be discovered in patients with C3GN. Explaining C3GN pathogenesis is challenging; therefore, additional research is required in the future.

Sex-Specific Complement and Cytokine Imbalances in Drug-Resistant Epilepsy: Biomarkers of Immune Vulnerability.

Drug-resistant epilepsy (DRE) poses significant challenges in treatment and management. While seizure-related alterations in peripheral immune players are increasingly recognized, the involvement of the complement system, central to immune function, remains insufficiently explored in DRE. This study aimed to investigate the levels of complement system components and their association with cytokine profiles in patients with DRE. We analyzed serum samples from DRE patients (n = 46) and age- and sex-matched healthy controls (n = 45). Complement components and cytokines were quantified using Multi- and Single-plex ELISA. Statistical analyses examined relationships between complement molecules, cytokines, and clinical outcomes including epilepsy duration, Full-Scale Intelligence Quotient (FSIQ) scores, and age. We found common alterations in all DRE cases, including significant complement deficiencies (C1q, Factor H, C4, C4b, C3, and C3b/iC3b) and detectable bFGF levels. DRE females showed significantly lower levels of TNFα and IL-8 compared to healthy females. We observed a trend towards elevated CCL2 and CCL5 levels in DRE males compared to healthy males. These findings suggest potential sex dimorphism in immune profiles. Our analysis also indicated associations between specific complement and inflammatory markers (C2, IL-8, and IL-9) and Full-Scale Intelligence Quotient (FSIQ) scores in DRE patients. Our study reveals sex-specific peripheral complement deficiencies and cytokine dysregulation in DRE patients, indicating an underlying immune system vulnerability. These findings provide new insights into DRE mechanisms, potentially guiding future research on complement and cytokine signaling toward personalized treatments for DRE patients.

Relapsed Bacterial Meningitis in an Adolescent Patient with Aberrant Patent Foramen Caecum

Bacterial meningitis is a serious life-threatening condition. Recurrent meningitis is defined as two independent episodes of meningitis that are separated by a period of convalescence and full recovery. Therefore, true recurrence results from a re-infection with the same or a different bacterial organism. In contrast, recrudescence and relapsed meningitis (RBM) represent persistence of the initial infection resulting from treatment failure. Both are uncommon and could be due to anatomic anomalies of the skull, traumatic head injury with secondary CSF fistula, complement deficiency or spread from a para meningeal infection.

Immunodeficiency: Complement disorders.

The complement system is an important component of innate and adaptive immunity that consists of three activation pathways. The classic complement pathway plays a role in humoral immunity, whereas the alternative and lectin pathways augment the innate response. Impairment, deficiency, or overactivation of any of the known 50 complement proteins may lead to increased susceptibility to infection with encapsulated organisms, autoimmunity, hereditary angioedema, or thrombosis, depending on the affected protein. Classic pathway defects result from deficiencies of complement proteins C1q, C1r, C1s, C2, and C4, and typically manifest with features of systemic lupus erythematosus and infections with encapsulated organisms. Alternative pathway defects due to deficiencies of factor B, factor D, and properdin may present with increased susceptibility to Neisseria infections. Lectin pathway defects, including Mannose-binding protein-associated serine protease 2 (MASP2) and ficolin 3, may be asymptomatic or lead to pyogenic infections and autoimmunity. Complement protein C3 is common to all pathways, deficiency of which predisposes patients to severe frequent infections and glomerulonephritis. Deficiencies in factor H and factor I, which regulate the alternative pathway, may lead to hemolytic uremic syndrome. Disseminated Neisseria infections result from terminal pathway defects (i.e., C5, C6, C7, C8, and C9). Diagnosis of complement deficiencies involves screening with functional assays (i.e., total complement activity [CH50], alternative complement pathway activity [AH50], enzyme-linked immunosorbent assay [ELISA]) followed by measurement of individual complement factors by immunoassay. Management of complement deficiencies requires a comprehensive and individualized approach with special attention to vaccination against encapsulated bacteria, consideration of prophylactic antibiotics, treatment of comorbid autoimmunity, and close surveillance.

Relapsed Bacterial Meningitis in an Adolescent Patient with Aberrant Patent Foramen Caecum

Bacterial meningitis is a serious life-threatening condition. Recurrent meningitis is defined as two independent episodes of meningitis that are separated by a period of convalescence and full recovery. Therefore, true recurrence results from a re-infection with the same or a different bacterial organism. In contrast, recrudescence and relapsed meningitis (RBM) represent persistence of the initial infection resulting from treatment failure. Both are uncommon and could be due to anatomic anomalies of the skull, traumatic head injury with secondary CSF fistula, complement deficiency or spread from a para meningeal infection.

Monogenic lupus with neuroregression in an infant due to rare compound heterozygous variants in C1QA gene: Case based review.

Monogenic lupus is a rare variant of systemic lupus erythematosus (SLE) that develops in patients with a single gene disorder. Early complement component deficiencies were the first forms of monogenic lupus to be described and C1Q gene mutations are one of the most common forms. C1QA complement deficiency has been reported to occur usually due to biallelic variants in C1QA gene and compound heterozygous variants in C1QA gene have rarely been reported. Majority of the monogenic lupus patients with C1Q deficiency present with mucocutaneous, renal, and musculoskeletal manifestations. Our patient is an unusual case of monogenic lupus with severe neurological manifestations along with cutaneous, haematological, and hepatic manifestations secondary to rare compound heterozygous variants in C1QA gene and anti-ribosomal P autoantibody positivity. She was treated with glucocorticoids, rituximab and fresh frozen plasma with partial neurological recovery. Thus, we present a unique case of monogenic lupus due to a rare compound heterozygous variant in C1QA gene with a brief review of literature.

Lupus nephritis and thrombotic microangiopathy: A review

Lupus nephritis (LN) is one of the most common organ-specific manifestations of systemic lupus erythematosus (SLE). Various clinical signs of LN develop in at least 50% of patients with SLE. In addition to LN, the spectrum of renal lesions associated with SLE also includes vascular pathology. One of the variants of renal microvascular injury is thrombotic microangiopathy (TMA), the mechanisms of which are diverse. The review focuses on the main forms of TMA, including antiphospholipid syndrome and nephropathy associated with antiphospholipid syndrome, TMA caused by complement system regulation disorders and deficiency of ADAMTS13. In most cases, these forms of TMA are combined with LN. However, they may also exist as a single form of kidney damage. This article discusses the TMA pathogenesis, the impact on kidney prognosis, and treatment options.

Complement or insult: the emerging link between complement cascade deficiencies and pathology of myeloid malignancies.

The complement cascade is an ancient and highly conserved arm of the immune system. The accumulating evidence highlights elevated activity of the complement cascade in cancer microenvironment and emphasizes its effects on the immune, cancer, and cancer stroma cells, pointing to a role in inflammation-mediated etiology of neoplasms. The role the cascade plays in development, progression, and relapse of solid tumors is increasingly recognized, however its role in hematological malignancies, especially those of myeloid origin, has not been thoroughly assessed and remains obscure. As the role of inflammation and autoimmunity in development of myeloid malignancies is becoming recognized, in this review we focus on summarizing the links that have been identified so far for complement cascade involvement in the pathobiology of myeloid malignancies. Complement deficiencies are primary immunodeficiencies that cause an array of clinical outcomes including an increased risk of a range of infectious as well as local or systemic inflammatory and thrombotic conditions. Here, we discuss the impact that deficiencies in complement cascade initiators, mid- and terminal-components and inhibitors have on the biology of myeloid neoplasms. The emergent conclusions indicate that the links between complement cascade, inflammatory signaling, and the homeostasis of hematopoietic system exist, and efforts should continue to detail the mechanistic involvement of complement cascade in the development and progression of myeloid cancers.

#2113 Membranoproliferative glomerulonephritis experience over 20 years in a tertiary centre in the United Kingdom

Abstract Background and Aims Membranoproliferative Glomerulonephritis (MPGN) is a histological pattern of injury which typically accounts for light microscopy findings on 1-3% of kidney biopsies. It is classified based on immunofluorescence into complement-mediated, immune complex-mediated (IC) and immunofluorescence negative. The underlying aetiologies such as C3 Glomerulopathy are rare diseases, and thus longitudinal real-world experience in terms of underlying causes, treatment and outcomes is valuable. Method This study presents a retrospective review of biopsy data from January 2000 through to December 2020 in a tertiary renal referral centre in the United Kingdom (UK). This review was conducted using the organisation's biopsy database, with patient demographics and clinical information obtained from the Electronic Patient Record. All patients with an MPGN pattern on biopsy were reviewed. Those with new MPGN post-transplant, with an MPGN pattern on biopsy but subsequently diagnosed as IgA Nephropathy, and with an MPGN pattern but a known lupus diagnosis, were excluded. Results A histological finding of MPGN on kidney biopsy was found in 67 patients. Of these, 41 remained in the study following application of the exclusion criteria, with an additional 3 excluded as there was insufficient information available for classification in their biopsy reports. Of the 38 remaining, 28 had IC MPGN and 10 had C3 Glomerulopathy (C3G) - 8 with C3 Glomerulonephritis (C3GN) and 2 with C3 Dense Deposit Disease (DDD). Median follow up was 72 (range 45-126) months. Median age was 64 years in the IC MPGN and 55 years in the C3G groups (p 0.125). The majority in both groups were female, 60.7% (17) and 60% (6) respectively. There was no significant difference in renal function, blood pressure, or proteinuria at presentation between the groups. MPGN was associated with infections in 8 patients (21.1%), connective tissue disease in 3 patients (7.9%), monoclonal gammopathies or haematological malignancies in 8 patients (21.1%), and 2 had identified complement deficiencies (5.3%). Over the study period 47.4% (18) of patients progressed to end stage kidney disease and 50% (19) died. There was no significant difference in these outcomes between the IC MPGN and the C3G groups. Progression to renal replacement therapy (RRT) was seen in 42.9% (12) of the IC MPGN group, and 60% (6) of the C3G group (p=0.287). This included two patients who received a kidney transplant (both in the C3G group), one of whom developed recurrence during the available follow up. Conclusion This study adds a UK perspective with long term data and outcomes in a rare condition. Almost half of patients progressed to RRT and half of patients died during the follow-up period. These outcomes were seen at similar rates in those with IC MPGN and those with C3G. A variety of associated conditions were observed, and the low number of complement deficiencies identified is likely due to the historical nature of the review with reduced screening for complement abnormalities and genetics in the earlier period. Outcomes on follow-up:

Evaluating the performance of optilite® C1Q and C2 turbidimetric assays in patients with complement deficiency or undergoing complement inhibitor therapy

Evaluating the performance of optilite® C1Q and C2 turbidimetric assays in patients with complement deficiency or undergoing complement inhibitor therapy

Use of the Pfizer Pentavalent Meningococcal Vaccine Among Persons Aged ≥10 Years: Recommendations of the Advisory Committee on Immunization Practices - United States, 2023.

Meningococcal disease is a life-threatening invasive infection caused by Neisseria meningitidis. Two quadrivalent (serogroups A, C, W, and Y) meningococcal conjugate vaccines (MenACWY) (MenACWY-CRM [Menveo, GSK] and MenACWY-TT [MenQuadfi, Sanofi Pasteur]) and two serogroup B meningococcal vaccines (MenB) (MenB-4C [Bexsero, GSK] and MenB-FHbp [Trumenba, Pfizer Inc.]), are licensed and available in the United States and have been recommended by CDC's Advisory Committee on Immunization Practices (ACIP). On October 20, 2023, the Food and Drug Administration approved the use of a pentavalent meningococcal vaccine (MenACWY-TT/MenB-FHbp [Penbraya, Pfizer Inc.]) for prevention of invasive disease caused by N. meningitidis serogroups A, B, C, W, and Y among persons aged 10-25 years. On October 25, 2023, ACIP recommended that MenACWY-TT/MenB-FHbp may be used when both MenACWY and MenB are indicated at the same visit for the following groups: 1) healthy persons aged 16-23 years (routine schedule) when shared clinical decision-making favors administration of MenB vaccine, and 2) persons aged ≥10 years who are at increased risk for meningococcal disease (e.g., because of persistent complement deficiencies, complement inhibitor use, or functional or anatomic asplenia). Different manufacturers' serogroup B-containing vaccines are not interchangeable; therefore, when MenACWY-TT/MenB-FHbp is used, subsequent doses of MenB should be from the same manufacturer (Pfizer Inc.). This report summarizes evidence considered for these recommendations and provides clinical guidance for the use of MenACWY-TT/MenB-FHbp.

Mendelian Causes of Autoimmunity: the Lupus Phenotype.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is characterized by its large heterogeneity in terms of clinical presentation and severity. The pathophysiology of SLE involves an aberrant autoimmune response against various tissues, an excess of apoptotic bodies, and an overproduction of type-I interferon. The genetic contribution to the disease is supported by studies of monozygotic twins, familial clustering, and genome-wide association studies (GWAS) that have identified numerous risk loci. In the early 70s, complement deficiencies led to the description of familial forms of SLE caused by a single gene defect. High-throughput sequencing has recently identified an increasing number of monogenic defects associated with lupus, shaping the concept of monogenic lupus and enhancing our insights into immune tolerance mechanisms. Monogenic lupus(moSLE) should be suspected in patients with either early-onset lupus or syndromic lupus, in male, or in familial cases of lupus. This review discusses the genetic basis of monogenic SLE and proposes its classification based on disrupted pathways. These pathways include defects in the clearance of apoptotic cells or immune complexes, interferonopathies, JAK-STATopathies, TLRopathies, and T and B cell dysregulations.

Complement Suppresses the Initial Type 1 Interferon Response to Ocular Herpes Simplex Virus Type 1 Infection in Mice.

The complement system (CS) contributes to the initial containment of viral and bacterial pathogens and clearance of dying cells in circulation. We previously reported mice deficient in complement component 3 (C3KO mice) were more sensitive than wild-type (WT) mice to ocular HSV-1 infection, as measured by a reduction in cumulative survival and elevated viral titers in the nervous system but not the cornea between days three and seven post infection (pi). The present study was undertaken to determine if complement deficiency impacted virus replication and associated changes in inflammation at earlier time points in the cornea. C3KO mice were found to possess significantly (p < 0.05) less infectious virus in the cornea at 24 h pi that corresponded with a decrease in HSV-1 lytic gene expression at 12 and 24 h pi compared to WT animals. Flow cytometry acquisition found no differences in the myeloid cell populations residing in the cornea including total macrophage and neutrophil populations at 24 h pi with minimal infiltrating cell populations detected at the 12 h pi time point. Analysis of cytokine and chemokine content in the cornea measured at 12 and 24 h pi revealed that only CCL3 (MIP-1α) was found to be different between WT and C3KO mice with >2-fold increased levels (p < 0.05, ANOVA and Tukey's post hoc t-test) in the cornea of WT mice at 12 h pi. C3KO mouse resistance to HSV-1 infection at the early time points correlated with a significant increase in type I interferon (IFN) gene expression including IFN-α1 and IFN-β and downstream effector genes including tetherin and RNase L (p < 0.05, Mann-Whitney rank order test). These results suggest early activation of the CS interferes with the induction of the type I IFN response and leads to a transient increase in virus replication following corneal HSV-1 infection.

Inborn errors of immunity with kidney and urinary tract disorders: a review.

Human inborn errors of immunity (IEIs), previously referred to as primary immunodeficiency disorders (PIDs), are a heterogeneous spectrum of inherited abnormalities of the immune system with different organ involvement. The number of identified IEIs is rapidly increasing, highlighting the non-negligible role of an interdisciplinary approach in clinical diagnosis. Kidney disorders are one of the important comorbidities in some of the affected patients and play a significant role in the diagnosis and course of disease. According to recent studies, 22 types of human IEI with renal manifestations have been identified so far, including immunodeficiency with congenital thrombocytopenia, thymic defects with additional congenital anomalies, complement deficiencies, type 1 interferonopathies, immunity related to non-hematopoietic tissues, congenital neutropenia's, common variable immunodeficiency disorder (CVID) phenotype and immuno-osseous dysplasia. Based on this classification, we herein review IEIs with renal features and explain the genetic defect, inheritance, and type of renal manifestations.

Usefulness and analytical performances of complement multiplex assay for measuring complement biomarkers in plasma

IntroductionThe complement system is involved in numerous diseases, through diverse mechanisms and degree of activation. With the emergence of complement targeting therapeutic, simple and accessible tools to evaluate the extent of complement activation are strongly needed. MethodsWe evaluated two multiplex panels, measuring complement activation fragments (C4a, C3a, C5a, Bb, Ba, sC5b9) and intact components or regulators (C1q, C2, C3, C4, C5, FD, FP, FH, FI). The specificity of each measurement was assessed by using complement proteins depleted sera and plasma collected from patients with complement deficiencies. Normal values distribution was estimated using 124 plasma samples from healthy donors and complement activation profile was assessed in plasma collected from 31 patients with various complement-mediated disorders. ResultsWe observed good inter-assay variation. All tested protein deficiencies were accurately detected. We established assay-specific reference values for each analyte. Except for C3, C4 and C4a, the majority of the measurements were in good agreement with references methods or published data. ConclusionOur study substantiates the utility of the Complement Multiplex assay as a tool for measuring complement activation and deficiencies. Quantifying complement cleavage fragments in patients exhibiting classical or alternative pathway activation allowed evaluating the activation state of the whole cascade.

Hereditary Angioedema- A Rare Case Report and Literature Review

Hereditary angioedema (HAE) is a rare disorder due to either deficiency or dysfunction of Complement 1 (C1) esterase inhibitor (C1-INH). HAE usually presents with recurrent angioedema (AE) episodes affecting the extremities, face, and gastrointestinal tract, but it is not associated with urticarial rash and itching. Timely identification of this condition is vital because the lack of response to traditional antihistamines and steroids leads to a rise in mortality of up to 30%–40% in undiagnosed cases. Here, we present a case involving a 25-year-old woman, who presented with 1-day complaints of right upper limb swelling, which spread to involve all the limbs and her face within 12 h of symptom onset. She also had a history of abdominal pain, which was sudden in onset, squeezing type, without any associated vomiting and diarrhea. She denied a history of drug or food allergies. Given the presence of AE, we treated her with antihistamines and steroid injections, but she failed to respond. On asking, she gave a history from childhood of repeated episodes and similar complaints in her family members. With history and physical symptoms suggestive of HAE, diagnostic studies showed decreased complement 4 l (C4) and C1 INH levels, confirming the diagnosis of HAE Type 1. The patient was successfully managed with fresh-frozen plasma as first-line treatment options are unavailable in India. Due to a lack of clinical awareness, the disease often remains undiagnosed for several years. Thus, there is a high need to raise clinical awareness and diagnostic facilities to improve case detection and management of HAE.

Antibody Production after COVID-19 Vaccination in Patients with Inborn Errors of Immunity.

Few studies have evaluated COVID-19 vaccine efficacy in patients with inborn errors of immunity (IEI). To evaluate the levels of antibody (Ab) production and function after COVID-19 vaccination in IEI patients with phagocytic, complement, and Ab deficiencies and their comparison with healthy controls. Serum samples were collected from 41 patients and 32 healthy controls at least one month after the second dose of vaccination, while clinical evaluations continued until the end of the third dose. Levels of specific anti-receptor-binding domain (RBD) IgG and anti-RBD neutralizing antibodies were measured using EUROIMMUN and ChemoBind kits, respectively. Conventional SARS-CoV-2 neutralization test (cVNT) was also performed. Cutoff values of ≤20, 20-80, and ≥80 (for cVNT and Chemobined) and 0.8-4.2, 4.2-8.5, and ≥8.5 (for EUROIMMUN) were defined as negative/weak, positive/moderate, and positive/significant, respectively. A considerable distinction was observed between the Ab-deficient patients and the controls for Ab concentration (EUROIMMUN, p<0.01) and neutralization (ChemoBind, p<0.001). However, there was no significant difference compared with the other patient groups. A near-zero cVNT in Ab-deficient patients was found compared to the controls (p<0.01). A significant correlation between the two kits was found using the whole data (R2=0.82, p<0.0001). Despite varying degrees of Ab production, all Ab deficient patients, as well as almost half of those with complement and phagocytic defects, did not effectively neutralize the virus (cVNT). In light of the decreased production and efficiency of the vaccine, a revised immunization plan may be needed in IEI.

Clinical Implications of Germline Predisposition Gene Variants in Patients with Refractory or Relapsed B Acute Lymphoblastic Leukemia

Objectives:Gene variants are important factors in prognosis of the patients with hematological malignancies. In current study, our team investigate the relationship between blood and immune system germline predisposition variants and refractory/relapsed acute B lymphoblastic leukemia in patients. Methods:The study included 75 patients with refractory/recurrent acute B-lymphoblastic leukemia between January 2020 and December 2022. The first group of 41 patients, median age 13.5 years (range: 2-66 years), had not had a bone marrow transplant. The second group of 34 patients with a median age of 28.5 (range: 4-51 years old, once had a bone marrow transplant. More than 700 genetic susceptibility genes related to blood and immune system diseases were detected in all patient samples using high-throughput DNA sequencing technology to detect the type and number of Class I and Class II gene variants. The average sequencing depth was 150×. Class I refers to the gene variants that are clearly significant in guidelines or authoritative research literature. Class II are genetic variants that software analysis suggests may be harmful. Results:In the first group, 41 patients had an average number of Class I genetic susceptibility gene variants of 3.8 and Class II genetic susceptibility gene variants of 14.5 per patient. A total of 94 Class I genetic susceptibility gene variants were found, Thirty-two of them were recurrent more than 3 times that including HIF1A、SERPINE1、CFTR、CHEK2、ELANE、IFIH1、IRF7、JAK3、NCF2、PRF1、TGFBR2、TNFRSF13B、ATM、CYP3A4、ITGA2、NUDT15、THBD、BTLA、DNASE1、MPEG1、ADAMTS13、EP300、FANCA、KIT、BRCA2、F7、MLH1、STK11、TP53、YARS2、CYP2C19、TNFAIP3. The functions of these genes involve in combined immunodeficiency, autoinflammatory disease, complement deficiency, immune deficiency, T-cell dysfunction and antibody deficiency. After remission by CART cell therapy, twenty-three of the 41 patients underwent haploidentical hematopoietic stem cell transplantation, among which 5 patients relapsed after transplantation, three of the five donors of relapsed patients were also found HIF1A and SERPINE1 gene variants. In the second group of 34 patients, the average number of Class I genetic susceptibility gene variants in each patient was 3, and the average number of class 2 genetic susceptibility gene variants was 14. A total of 53 class 1 genetic susceptibility gene variants were found, Eleven of them were recurrent more than 3 times that Including BTLA、MPEG1 、KIT、SERPINE1、STK11、TP53、UGT1A1、EP300、FANCA、YARS2、F7,and four donors also carried the above gene variants, which were EP300. MPEG1, SERPINE1, YARS2 . After 34 patients achieved remission by CART cell therapy, 9 patients underwent the second hematopoietic stem cell transplantation (related half-matched), and 3 of them relapsed after the second transplantation (average 2.3 months). Two of the 3 donors of relapsed patients after second hematopoietic stem cell transplantation were also found BTLA and MPEG1 gene variants. Conclusions:Our results have shown that genetic susceptibility gene variants related to blood and immune system diseases are associated with refractory or relapsed acute B lymphoblastic leukemia. The number of genetic susceptibility gene variants may be related to the relapse of leukemia. 32 Class I genetic susceptibility gene variants may be related to the relapse of leukemia during chemotherapy, and 11 class I genetic susceptibility gene variants may be associated with relapse after bone marrow transplantation. Donor carrying genetic susceptibility gene variants (HIF1A and SERPINE1, EP300, MPEG1, YARS2, BTLA) may be associated with relapse after transplantation. Genetic susceptibility gene variants may also be helpful in the selection of bone marrow transplant donors. Keywords Acute lymphoblastic leukemia, germline predisposition gene, hematopoietic stem cell transplant, , relapse, hematological malignancy

Increased infiltration of CD4+ T cell in the complement deficient lymphedema model

BackgroundLymphedema is an intractable disease that can be caused by injury to lymphatic vessels, such as by surgical treatments for cancer. It can lead to impaired joint mobility in the extremities and reduced quality of life. Chronic inflammation due to infiltration of various immune cells in an area of lymphedema is thought to lead to local fibrosis, but the molecular pathogenesis of lymphedema remains unclear. Development of effective therapies requires elucidation of the immunological mechanisms involved in the progression of lymphedema. The complement system is part of the innate immune system which has a central role in the elimination of invading microbes and acts as a scavenger of altered host cells, such as apoptotic and necrotic cells and cellular debris. Complement-targeted therapies have recently been clinically applied to various diseases caused by complement overactivation. In this context, we aimed to determine whether complement activation is involved in the development of lymphedema.ResultsOur mouse tail lymphedema models showed increased expression of C3, and that the classical or lectin pathway was locally activated. Complement activation was suggested to be involved in the progression of lymphedema. In comparison of the C3 knockout (KO) mouse lymphedema model and wild-type mice, there was no difference in the degree of edema at three weeks postoperatively, but the C3 KO mice had a significant increase of TUNEL+ necrotic cells and CD4+ T cells. Infiltration of macrophages and granulocytes was not significantly elevated in C3 KO or C5 KO mice compared with in wild-type mice. Impaired opsonization and decreased migration of macrophages and granulocytes due to C3 deficiency should therefore induce the accumulation of dead cells and may lead to increased infiltration of CD4+ T cells.ConclusionsVigilance for exacerbation of lymphedema is necessary when surgical treatments have the potential to injure lymphatic vessels in patients undergoing complement-targeted therapies or with complement deficiency. Future studies should aim to elucidate the molecular mechanism of CD4+ T cell infiltration by accumulated dead cells.

Complement.

The role of complement in human autoimmune, inflammatory, and infectious diseases is reviewed, focusing on clinical applicability. A typical case is presented in which serum testing for C3 and C4 is performed to help assess a syndrome with a broad differential diagnosis. The review includes a discussion of complement deficiency states, consumption of complement by diseases characterized by immune-complex formation and deposition, usefulness and interpretation of laboratory tests for complement, and development of drugs targeting specific components of the complement pathway for a growing number of indications.