Progress in the field of antibody mediated rejection (ABMR) in kidney transplantation has shown a rapid increase during the past two decades. New pathologic entities have emerged and replace old concepts and diagnostic terms. According to newly acknowledged facts discovered by clinicians, researchers, and pathologists all over the world, an updated classification, rather than Banff 07, is needed. In order to improve the diagnostic accuracy for ABMR in clinicians as well as pathologists, recognition and awareness of various conditions such as C4d-negative ABMR, subclinical ABMR, de novo donor specific antibody, microcirculation inflammation, isolated vascular lesion, antibody-mediated transplant arteriopathy, etc. are essentially important.
Antibodies ; Complement C4b ; Graft Rejection ; Humans ; Inflammation ; Kidney ; Kidney Transplantation ; Microcirculation ; Peptide Fragments ; Rejection (Psychology) ; Tissue Donors ; Transplants

C4d deposition in peritubular capillaries in renal allograft biopsies is a significant marker for diagnosis of antibody-mediated rejection. However, it is unclear whether C4d deposition could be derived from BK virus infection. We present a case of BK virus nephropathy with strong C4d deposition 10 months after kidney transplantation. The diagnosis of BK virus nephropathy was missed out, whereas strong C4d deposition was noted in the first biopsy and therefore anti-rejection therapy was started. The deterioration of renal function led to a evaluate the possibility of BK virus nephropathy with second graft biopsy and further studies of BK virus replication status. Second graft biopsy revealed BK virus nephropathy without rejection. Finally, discontinuation of immunosuppressants and addition of anti-viral therapy for BK virus resulted in recovery of renal function, despite development of pancytopenia and subsequent fungal infection after leflunomide therapy. As in this case, initial focal pathologic changes from BK virus nephropathy could be overlooked by light microscopy. In addition, even though C4d positivity in peritubular capillaries is a good marker for diagnosis of antibody-mediated rejection, the meticulous examinations of the localization of C4d is needed, considering BK virus activates complement pathways and therefore leads to deposition of C4d mainly in tubular basement membrane. Based on our case of BK virus nephropathy with strong C4d deposition, we suggest that C4d deposition could be derived from BK virus nephropathy and therefore, it should be differentiated from acute antibody- mediated rejection in a renal allograft recipient.
Basement Membrane ; Biopsy ; BK Virus ; Capillaries ; Complement C4b ; Complement System Proteins ; Immunosuppression ; Immunosuppressive Agents ; Isoxazoles ; Kidney Transplantation ; Light ; Microscopy ; Pancytopenia ; Peptide Fragments ; Rejection (Psychology) ; Transplantation, Homologous ; Transplants

A 66-year-old male was admitted for increasing azotemia. He was diagnosed with chronic antibody- mediated rejection and had received a livingdonor renal transplant from his 32-year-old son prior to his admission. The peritubular capillaries of his kidney were diffusely positive on C4d immunostaining. It is known that there is an agreement between C4d staining and serological and histopathological data during rejection that is thought to have a humoral component. The role of alloantibodies in chronic renal allograft deterioration and the corresponding morphologic changes have been increasingly recognized during the recent years. However the treatment guidelines for chronic antibody-mediated rejection have not yet been established. Intravenous immunoglobulin (IVIG) has been shown to decrease the titers of anti-HLA antibodies in highly sensitized patients awaiting transplant. There are also numerous proposed mechanisms regarding how IVIG exerts its immunomodulatory action. As we have experienced chronic antibody-mediated rejection and how IVIG treatment improves renal function, we recognize that IVIG has the potential to be used for treating certain subgroups of chronic allograft nephropathy patients with positive C4d staining and anti-HLA antibodies.
Adult ; Aged ; Antibodies ; Azotemia ; Capillaries ; Complement C4b ; HLA Antigens ; Humans ; Immunoglobulins ; Immunoglobulins, Intravenous ; Isoantibodies ; Kidney ; Male ; Peptide Fragments ; Rejection (Psychology) ; Transplantation, Homologous ; Transplants

Donor-specific anti-human leukocyte antigen antibodies (DSA) following kidney transplantation predict the evolution of humoral rejection and reduced graft survival. Rapid, complete elimination of DSA during antibody-mediated rejection (AMR) is rarely achieved with traditional antihumoral therapies. We report the case of a 39-year-old female who was admitted for increasing azotemia and diagnosed with AMR based on diffusely positive histological changes on C4d immunostaining. In this case, bortezomib reversed the histological changes and induced a reduction in DSA. Proteasome-inhibitor-based combination therapy is a potential means for rapid DSA elimination in antibody-mediated rejection in renal transplant recipients.
Adult ; Antibodies ; Azotemia ; Boronic Acids ; Complement C4b ; Female ; Graft Survival ; HLA Antigens ; Humans ; Kidney Transplantation ; Leukocytes ; Peptide Fragments ; Proteasome Inhibitors ; Pyrazines ; Rejection (Psychology) ; Transplants ; Bortezomib

Donor-specific anti-human leukocyte antigen antibodies (DSA) following kidney transplantation predict the evolution of humoral rejection and reduced graft survival. Rapid, complete elimination of DSA during antibody-mediated rejection (AMR) is rarely achieved with traditional antihumoral therapies. We report the case of a 39-year-old female who was admitted for increasing azotemia and diagnosed with AMR based on diffusely positive histological changes on C4d immunostaining. In this case, bortezomib reversed the histological changes and induced a reduction in DSA. Proteasome-inhibitor-based combination therapy is a potential means for rapid DSA elimination in antibody-mediated rejection in renal transplant recipients.
Adult ; Antibodies ; Azotemia ; Boronic Acids ; Complement C4b ; Female ; Graft Survival ; HLA Antigens ; Humans ; Kidney Transplantation ; Leukocytes ; Peptide Fragments ; Proteasome Inhibitors ; Pyrazines ; Rejection (Psychology) ; Transplants ; Bortezomib

OBJECTIVETo explore the significance of C4d deposition in follicular lymphoma (FL).

METHODSThe deposition of C4d was detected in samples from 133 cases of lymphoma by immunohistochemistry and FL was studied by the double stainings of CD35/C4d, CD21/C4d and Bcl-2/C4d,respectively.

RESULTSAmong the 26 FL tissues, irregular C4d deposition was seen in 19 tumor tissues. Double staining for CD35, CD21 or Bcl-2 showed the C4d deposition was around the follicular dendritic cells (FDC). There was no significant difference between the positive rate of C4d and the degree of lymphoma. No deposition was found in the diffuse areas of FL and other type lymphomas.

CONCLUSIONC4d deposition around the follicular dendritic cell in the neoplastic follicles is a specific indicator of follicular lymphoma.

Adolescent ; Adult ; Aged ; Aged, 80 and over ; Complement C4b ; immunology ; Female ; Humans ; Immunohistochemistry ; Lymphoma, Follicular ; immunology ; pathology ; Male ; Middle Aged ; Peptide Fragments ; immunology

Antibodies ; immunology ; Antibody Formation ; Complement C4b ; immunology ; pharmacology ; Diagnosis ; Graft Rejection ; diagnosis ; immunology ; Humans ; Kidney Transplantation ; immunology ; Peptide Fragments ; immunology ; pharmacology ; Transplantation, Homologous ; immunology

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

BACKGROUND: The complement system plays an important role in the immune response to transplantation, and the diagnostic significance of peritubular capillary (PTC) C4d deposition (C4d+) in grafts is controversial. The study aimed to fully investigate the risk factors for PTC C4d+ and analyze its significance in biopsy pathology of kidney transplantation. METHODS: This retrospective study included 124 cases of kidney transplant with graft biopsy and donor-specific antibody (DSA) testing from January 2017 to December 2019 in a single center. The effects of recipient pathological indicators, eplet mismatch (MM), and DSAs on PTC C4d+ were examined using univariate and multivariate logistic regression analyses. RESULTS: In total, 35/124 (28%) were PTC C4d+, including 21 with antibody-mediated rejection (AMR), eight with renal tubular injury, three with T cell-mediated rejection, one with glomerular disease, and two others. Univariate analysis revealed that DSAs (P < 0.001), glomerulitis (P < 0.001), peritubular capillaritis (P < 0.001), and human leukocyte antigen (HLA) B eplet MM (P = 0.010) were the influencing factors of PTC C4d+. According to multivariate analysis, DSAs (odds ratio [OR]: 9.608, 95% confidence interval [CI]: 2.742-33.668, P < 0.001), glomerulitis (OR: 3.581, 95%CI: 1.246-10.289, P = 0.018), and HLA B eplet MM (OR: 1.166, 95%CI: 1.005-1.353, P = 0.042) were the independent risk factors for PTC C4d+. In receiver operating characteristic curve analysis, the area under the curve was increased to 0.831 for predicting PTC C4d+ when considering glomerulitis, DSAs, and HLA B eplet MM. The proportions of HLA I DSAs and PTC C4d+ in active antibody-mediated rejection were 12/17 and 15/17, respectively; the proportions of HLA class II DSAs and PTC C4d+ in chronic AMR were 8/12 and 7/12, respectively. Furthermore, the higher the PTC C4d+ score was, the more serious the urinary occult blood and proteinuria of recipients at the time of biopsy. CONCLUSIONS PTC C4d+ was mainly observed in AMR cases. DSAs, glomerulitis, and HLA B eplet MM are the independent risk factors for PTC C4d+.
Allografts ; Biopsy ; Complement C4b ; Graft Rejection ; HLA Antigens ; HLA-B Antigens ; Humans ; Kidney Transplantation/adverse effects* ; Peptide Fragments ; Retrospective Studies ; Risk Factors

Proteins of the complement system are known to interact with many charged substances. We recently characterized binding of C1q and factor H to immobilized and liposomal anionic phospholipids. Factor H inhibited C1q binding to anionic phospholipids, suggesting a role for factor H in regulating activation of the complement classical pathway by anionic phospholipids. To extend this finding, we examined interactions of C1q and factor H with lipid A, a well-characterized activator of the classical pathway. We report that C1q and factor H both bind to immobilized lipid A, lipid A liposomes and intact Escherichia coli TG1. Factor H competes with C1q for binding to these targets. Furthermore, increasing the factor H: C1q molar ratio in serum diminished C4b fixation, indicating that factor H diminishes classical pathway activation. The recombinant forms of the Cterminal, globular heads of C1q A, B and C chains bound to lipid A and E. coli in a manner qualitatively similar to native C1q, confirming that C1q interacts with these targets via its globular head region. These observations reinforce our proposal that factor H has an additional complement regulatory role of down-regulating classical pathway activation in response to certain targets. This is distinct from its role as an alternative pathway down-regulator. We suggest that under physiological conditions, factor H may serve as a downregulator of bacterially-driven inflammatory responses, thereby fine-tuning and balancing the inflammatory response in infections with Gram-negative bacteria.
Binding, Competitive ; immunology ; Complement Activation ; immunology ; Complement C1q ; chemistry ; immunology ; metabolism ; Complement C4b ; analysis ; Complement Factor H ; chemistry ; immunology ; metabolism ; Complement Pathway, Classical ; immunology ; Escherichia coli ; immunology ; metabolism ; Humans ; Iodine Radioisotopes ; Isotope Labeling ; Lipid A ; immunology ; metabolism ; Liposomes ; immunology ; metabolism ; Protein Binding ; immunology ; Recombinant Proteins ; chemistry ; immunology ; metabolism ; Substrate Specificity