A 10-year-old girl was admitted with a 38-hour history of widespread subcutaneous petechiae and hematuria and a 6-hour history of jaundice and oliguria. Physical examination revealed widespread subcutaneous petechiae and jaundice of the skin and sclera. Laboratory tests showed anemia, thrombocytopenia, acute kidney injury, and markedly elevated lactate dehydrogenase. Thrombotic microangiopathy was initially diagnosed, with a high suspicion of atypical hemolytic uremic syndrome (aHUS). Eculizumab was initiated within 9 hours of admission (within 48 hours of onset). After the first infusion, hemolysis rapidly ceased, and the platelet count and renal function gradually returned to normal. Whole-exome sequencing identified homozygous deletions of <i>CFHR1i> exon 2 and <i>CFHR4i> exon 1. aHUS typically has abrupt onset and rapid progression. Clinicians should maintain high suspicion for aHUS when the triad of thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury is present. Ultra-early eculizumab (within 48 hours of onset) rapidly blocks complement-mediated thrombotic microangiopathy, reverses organ injury, and improves long-term prognosis. Additionally, complement-related genetic testing is important for etiological clarification and individualized determination of eculizumab treatment duration.
Humans ; Antibodies, Monoclonal, Humanized/administration & dosage* ; Female ; Atypical Hemolytic Uremic Syndrome/drug therapy* ; Child ; Complement C3b Inactivator Proteins

Hereditary angioedema (HAE) is a rare,unpredictable,autosomal dominant disorder characterized by recurrent swelling in subcutaneous and submucosal tissue.In recent years,the pathophysiology and pathogenesis of HAE have been continuously studied and elucidated.In addition to the genes encoding complement 1 esterase inhibitors,new pathogenic variants have been identified in the genes encoding coagulation factor Ⅻ,plasminogen,angiopoietin-1,kininogen,heparan sulfate 3-O-sulfotransferase 6,and myoferlin in HAE.Moreover,different pathogenic variants have different mechanisms in causing HAE.In addition,the pathogenic genes of some patients remain unknown.This review summarizes the recent progress in the classification,epidemiology,pathophysiology,and pathogenesis of HAE,aiming to provide ideas for further fundamental research,clinical diagnosis,and drug development of HAE.
Humans ; Angioedemas, Hereditary/diagnosis* ; Angiopoietin-1/metabolism* ; Plasminogen/metabolism* ; Kininogens/metabolism* ; Complement C1 Inhibitor Protein/metabolism*

To study the interaction between C4b-binding protein (C4BP) and Riemerella anatipestifer (RA), we cloned duck C4BPα, conducted prokaryotic expression and prepared the polyclonal antibody by immunizing mice. Then indirect immunofluorescence assay and dot blotting hybridization assay were used to verify the interaction between C4BP and RA. The full length of duck C4BPα nucleotide sequence was 1 230 bp, with the highest similarity to chicken C4BPα (82.1%). Phylogenetic tree analysis showed that duck C4BPα and chicken C4BPα were on the same phylogenetic tree branch and the genetic evolution relationship between them was the closest. C4BPα was efficiently expressed in Escherichia coli BL21 (DE3). The recombinant proteins existed in intracellular soluble form. The titer of polyclonal antibody was more than 1:10 000 and polyclonal antibodies could specifically recognize the recombinant proteins. The results of indirect immunofluorescence assay and dot blot hybridization assay showed that RA could interact with duck C4BP. The results provide a basis to further reveal the pathogenesis of RA.
Animals ; Cloning, Molecular ; Complement C4b-Binding Protein ; chemistry ; genetics ; metabolism ; Ducks ; classification ; genetics ; microbiology ; Gene Expression Regulation ; Mice ; Phylogeny ; Riemerella ; metabolism

OBJECTIVE: To screen potential plasma protein biomarkers for the progression of cervical precancerous lesions into cervical carcinoma and analyze their functions. METHODS: Plasma samples obtained from healthy control subjects, patients with low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial lesion (HSIL), cervical cancer (CC), and patients with CC after treatment were enriched for low-abundance proteins for liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. The MS data of the samples were analyzed using Discoverer 2.2 software, and the differential proteins (peptide coverage ≥20%, unique peptides≥2) were screened by comparison of LSIL, HSIL and CC groups against the control group followed by verification using target proteomics technology. Protein function enrichment and coexpression analyses were carried out to explore the role of the differentially expressed proteins as potential biomarkers and their pathological mechanisms. RESULTS: Compared with the control group, both LSIL group and HSIL group showed 9 differential proteins; 5 differentially expressed proteins were identified in CC group. The proteins ORM2 and HPR showed obvious differential expressions in LSIL and HSIL groups compared with the control group, and could serve as potential biomarkers for the progression of cervical carcinoma. The expression of F9 increased consistently with the lesion progression from LSIL to HSIL and CC, suggesting its value as a potential biomarker for the progression of cervical cancer. CFI and AFM protein levels were obviously decreased in treated patients with CC compared with the patients before treatment, indicating their predictive value for the therapeutic efficacy. Protein function enrichment analysis showed that all these differentially expressed proteins were associated with the complement system and the coagulation cascades pathway. CONCLUSIONS We identified 5 new protein biomarkers (F9, CFI, AFM, HPR, and ORM2) for cervical precancerous lesions and for prognostic evaluation of CC, and combined detection of these biomarkers may help in the evaluation of the development and progression of CC and also in improving the diagnostic sensitivity and specificity of cervical lesions.
Antigens, Neoplasm ; blood ; Biomarkers, Tumor ; blood ; Carrier Proteins ; blood ; Case-Control Studies ; Cervical Intraepithelial Neoplasia ; blood ; diagnosis ; Chromatography, Liquid ; Complement Factor I ; analysis ; Early Detection of Cancer ; Female ; Glycoproteins ; blood ; Haptoglobins ; Humans ; Neoplasm Proteins ; blood ; Orosomucoid ; analysis ; Precancerous Conditions ; blood ; diagnosis ; Serum Albumin, Human ; Tandem Mass Spectrometry ; Uterine Cervical Neoplasms ; blood ; diagnosis

Atypical hemolytic uremic syndrome (aHUS), a rare form of thrombotic microangiopathy, is distinguished from the typical form by the absence of a preceding verotoxin-producing Escherichia coli infection. Notably, aHUS occurs in association with genetic or acquired disorders causing dysregulation of the alternative complement pathway. Patients with aHUS may show the presence of anti-complement factor H (CFH) autoantibodies. This acquired form of aHUS (anti-CFH-aHUS) primarily affects children aged 9–13 years. We report a case of a 13-year-old Lao girl with clinical features of aHUS (most likely anti-CFH-aHUS). The initial presentation of the patient met the classical clinical triad of thrombotic microangiopathy (microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury) without preceding diarrheal illness. Low serum levels of complement 3 and normal levels of complement 4 indicated abnormal activation of the alternative complement pathway. Plasma infusion and high-dose corticosteroid therapy resulted in improvement of the renal function and hematological profile, although the patient subsequently died of infectious complications. This is the first case report that describes aHUS (possibly anti-CFH-aHUS) in Laos.
Adolescent ; Anemia, Hemolytic ; Atypical Hemolytic Uremic Syndrome ; Autoantibodies ; Child ; Complement C3 ; Complement C4 ; Complement Factor H ; Complement Pathway, Alternative ; Female ; Humans ; Immunosuppression ; Kidney ; Laos ; Plasma ; Shiga-Toxigenic Escherichia coli ; Thrombocytopenia ; Thrombotic Microangiopathies

Neisseria gonorrhoeae (NG), as a pathogen of gonorrhea, is strictly limited to growth on the human host. In case of gonococcal infection, the body may recruit such inflammatory cells as neutrophils to resist the invasion of NG or initiate its adaptive immune response by antigen presentation to eliminate the pathogen. However, a series of immune escape mechanisms of NG make it difficult to clear up the infection. In the innate immune system, NG can not only secrete thermonuclease to degrade neutrophile granulocytes, inhibit respiratory burst to resist killing by neutrophils, activate NLRP3 to prompt the pyronecrosis of inflammatory cells, but also regulate the differentiation of macrophages to reduce the inflammatory response, combine with factor H to evade complement-mediated killing. NG infection can hardly give rise to effective adaptive immune response and immune memory, but can promote TGF-β production to inhibit Th1/Th2-mediated adaptive immune response, bind to CEACAM1 on the B cell surface to promote apoptosis in B cells, and combine with CEACAM1 on the T cell surface to inhibit helper T cell proliferation, which makes it difficult for B cells to produce high-affinity specific antibodies. With the increasing drug-resistance of NG, immunological studies may play a significant role in the development of novel therapies and effective vaccines against the infection.
Adaptive Immunity ; Antibodies ; immunology ; Antigens, CD ; immunology ; Cell Adhesion Molecules ; immunology ; Complement Factor H ; immunology ; Gonorrhea ; immunology ; Humans ; Immune Evasion ; immunology ; Immunity, Innate ; immunology ; Neisseria gonorrhoeae ; immunology

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a rare disease that is often associated with genetic defects. Mutations of complement factor H (CFH) are the most common genetic defects that cause aHUS and often result in end-stage renal disease. Since CFH is mainly produced in the liver, liver transplantation (LT) has been performed in patients with defective CFH. METHODS: The clinical courses of four kidney allograft recipients who lost their native kidney functions due to aHUS associated with a CFH mutation were reviewed. RESULTS: Subject A underwent kidney transplantation (KT) twice, aHUS recurred and the allograft kidney failed within a few years. Subject B received a KT and soon experienced a recurrence of aHUS coinciding with infection. Her allograft kidney function has worsened, and she remains on plasma infusion therapy. Subject C underwent LT followed by KT. She is doing well without plasma infusion therapy after combined LT-KT for 3 years. Subject D received KT following LT and is now recurrence-free from aHUS. CONCLUSION: In patients with aHUS associated with a CFH mutation, KT without LT was complicated with a recurrence of aHUS, which might lead to allograft loss. Conversely, LT was successful in preventing the recurrence of aHUS and thus might be another option for a recurrence-free life for aHUS patients associated with CFH mutation.
Allografts ; Atypical Hemolytic Uremic Syndrome ; Complement Factor H ; Complement System Proteins ; Humans ; Kidney Failure, Chronic ; Kidney Transplantation ; Kidney ; Liver Transplantation ; Liver ; Plasma ; Rare Diseases ; Recurrence

OBJECTIVETo explore the characteristics in CFHR1 concentration and the frequency of CFHR1 gene polymorphisms of patients with type 2 diabetes mellitus (T2DM) based on the high level of complement factor H (CFH) expression among such patients and the similarity between CFHR1 and CFH in terms of sequence and functions.

METHODSFifty T2DM patients and 30 healthy controls were selected. The plasma samples were separated by pI with OFFGEL electrophoresis following solution digestion. Further separation and identification were carried out on a Nano HPLC-Chip-MS/MS system. Differentially expressed proteins were identified by comparison. Enzyme-linked immunosorbent assay (ELISA) was used to validate the result. Genomic DNA of the two groups was extracted. Polymerase chain reaction and sequencing were used to determine the single nucleotide polymorphisms in the 6 exons of the CFHR1 gene.

RESULTSThe CFHR1 level in plasma of T2DM patients were significantly higher than that of the healthy controls (P=2.78× 10). A significant difference in allelic frequencies of rs12406079 of the fifth exon of the CFHR1 gene was found between the two groups (χ=5.692, P=0.017).

CONCLUSIONThe concentration of CFHR1 and frequencies of CFHR1 gene polymorphisms among patients with T2DM differ significantly from healthy subjects. Polymorphisms of the CFHR1 gene are associated with T2DM.

Complement C3b Inactivator Proteins ; genetics ; metabolism ; Diabetes Mellitus, Type 2 ; genetics ; metabolism ; Female ; Genotype ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide

Hereditary angioedema is a disease of congenital deficiency or functional defect in the C1 esterase inhibitor (C1-INH) consequent to mutation in the SERPING1 gene, which encodes C1-INH. This disease manifests as recurrent, non-pitting, non-pruritic subcutaneous, or submucosal edema as well as an erythematous rash in some cases. These symptoms result from the uncontrolled localized production of bradykinin. The most commonly affected sites are the extremities, face, gastrointestinal tract, and respiratory system. When the respiratory system is affected by hereditary angioedema, swelling of the airway can restrict breathing and lead to life-threatening obstruction. Herein, we report a case of a 24-year-old woman with type 2 hereditary angioedema who presented with recurrent episodic abdominal pain and swelling of the extremities. She had no family history of angioedema. Although her C4 level was markedly decreased (3.40 mg/dL; normal range: 10-40 mg/dL), she presented with a very high C1-INH level (81.0 mg/dL; normal range: 21.0-39.0 mg/dL) and abnormally low C1-INH activity (less than 25%; normal range: 70%-130%). The SERPING1 gene mutation was confirmed in this patient. She was treated with prophylactic tranexamic acid, as needed, and subsequently reported fewer and less severe episodes. To our knowledge, this is the first reported case of type 2 hereditary angioedema in Korea that was consequent to SERPING1 mutation and involved a significantly elevated level of C1-INH as well as a low level of C1-INH activity.
Abdominal Pain ; Angioedema ; Angioedemas, Hereditary* ; Bradykinin ; Complement C1 Inhibitor Protein ; Edema ; Exanthema ; Extremities ; Female ; Gastrointestinal Tract ; Humans ; Korea ; Reference Values ; Respiration ; Respiratory System ; Tranexamic Acid ; Young Adult

PURPOSE: We investigated whether serum levels of insulin growth factor-1 (IGF-1) and insulin growth factor binding protein-3 (IGFBP-3) are valuable in predicting clinical outcomes or are correlated with other laboratory findings in children with Henoch-Schönlein purpura (HSP). METHODS: We examined 27 children who were consecutively admitted to our hospital with HSP between January 2011 and February 2012. Blood tests (C-reactive protein, white blood cell count, platelet count, erythrocyte sedimentation rate, albumin, immunoglobulin A, complement C3, antineutrophil cytoplasmic antibody, IGF-1, IGFBP-3) and urine tests were performed upon admission. IGF-1 and IGFBP-3 were resampled in the recovery phase. Controls included 473 children whose IGF-1 and IGFBP-3 were sampled for evaluating their growth, at the outpatient department of pediatric endocrinology in our hospital. IGF-1 and IGFBP-3 were compared between the HSP children and controls, and between the acute and recovery phases in HSP children. The ability of these values to predict clinical outcomes including renal involvement was analyzed using bivariate logistic regression analysis (BLRA). RESULTS: IGF-1 and IGFBP-3 were not different between the HSP children and controls (148.7±117.6 vs. 69.2±96.9, P=0.290: 3465.9±1290.9 vs. 3597.2±1,127.6, P=0.560, respectively). There was no significant difference in IGF-1 or IGFBP-3 between acute and recovery phases. Based on the BLRA, no variable, including IGF-1 and IGFBP-3, could predict clinical outcomes including the presence of nephritis. CONCLUSION: We concluded that IGF-1 and IGFBP-3 do not predict clinical outcomes of HSP, including renal involvement, in this study.
Antibodies, Antineutrophil Cytoplasmic ; Blood Sedimentation ; Child* ; Complement C3 ; Endocrinology ; Hematologic Tests ; Humans ; Immunoglobulin A ; Insulin* ; Insulin-Like Growth Factor Binding Protein 3 ; Insulin-Like Growth Factor I ; Leukocyte Count ; Logistic Models ; Nephritis ; Outpatients ; Platelet Count ; Purpura*