Ove J. Mellbye

Compstatin, a peptide inhibitor of C3, prolongs survival of ex vivo perfused pig xenografts

Fiane AE, Mollnes TE, Videm V, Hovig T, Høgåsen K, Mellbye OJ, Spruce L, Moore WT, Sahu A, Lambris JD. Compstatin, a peptide inhibitor of C3, prolongs survival of ex vivo perfused xenografts. Xenotransplantation 1999; 6: 000‐000 ©Munksgaard, Copenhagen

C1-inhibitor attenuates hyperacute rejection and inhibits complement, leukocyte and platelet activation in an ex vivo pig-to-human perfusion model.

Xenotransplantation may be a future alternative due to increased shortage of organs. Classical complement activation is central in hyperacute rejection in pig-to-human combinations. We investigated the effects of C1-inhibitor (C1-INH), a regulator of the complement and contact systems, on hyperacute rejection. Pig kidneys were perfused with fresh human blood to which either C1-INH (n = 6) or human serum albumin (n = 6) was added. The survival of the C1-INH perfused kidneys (mean 327 min) was significantly longer (p < 0.00001) than the controls (79 min). C1-INH substantially inhibited complement activation (C1rs-C1-INH complexes, C4bc, C3bc and terminal complement complex) (p < 0.001 for all) compared with the marked complement activation in the controls. No contact activation was found. Leukocytes and platelets were substantially activated (counts, myeloperoxidase, beta-thromboglobulin, thrombospondin, soluble P-selectin) in the control group, and this activation was markedly reduced by C1-INH (p < 0.02 for all). Immunohistochemistry showed less C1q, C3, TCC, IgG and fibrin deposition in the C1-INH group. C1-INH may be useful to attenuate hyperacute rejection, probably through inhibition of complement. The reduced activation of neutrophils and platelets may mainly be secondary to inhibition of complement.

Prolongation of Ex Vivo-Perfused Pig Xenograft Survival by the Complement Inhibitor Compstatin

HE COMPLEMENT system has been shown to play a central pathophysiologic role in hyperacute rejection (HAR) 1 and to contribute to the inflammation and organ injury associated with transplantation. 2 Recently, a novel phage-displayed C3-binding peptide (Compstatin) has been identified that suppresses complement activation and therefore may be of therapeutic value in clinical situations such as xenotransplantation that involve complement-mediated tissue damage. This peptide binds reversibly to the C3c portion of native C3 and inhibits both the classical and alternative pathways of complement activation. 3 Our results

Dermatomyositis Associated With BCG Vaccination

Two young boys developed serious forms of dermatomyositis following BCG vaccination. Possibilities of a causal relationship between the disease and the vaccination are discussed. Extensive immunological tests, however, including in vitro stimulation of lymphocytes with PPD, gave no decisive evidence of abnormalities. It is concluded that in cases of dermatomyositis there is an absolute indication for a full anamnesis with regard to previous vaccination, to obtain clarification of the practical and theoretically important questions of a possible connection in this respect.

Chronic Arthritis and gamma-Heavy Chain Disease: Coincidence or Pathogenic Link?

In 1991, gamma heavy chain disease was diagnosed in a 43-year-old female, who 3 years earlier had contracted an erosive seronegative chronic arthropathy. Her gamma heavy chain disease had a benign course, requiring no specific therapy for 5 years. In 1996, however, her lymphoproliferative disorder underwent a more malignant course, with renal and cardiac failure and increasing articular problems, requiring treatment with melphalan and prednisolone, following the protocol for myelomatosis. Laboratory studies revealed a monoclonal component in serum and urine. consistent with dimers of gamma-chains of the gamma3 subclass, but with a smaller molecular mass than normal gamma3-chains, suggesting molecular aberrations as consistently observed in this disorder. Massive localization of plasma cells and blasts with cytoplasmic or cell membrane staining for gamma3-chains, but no staining for kappa or lambda light chains, was observed by immunohistochemical studies of tissue specimens from bone marrow as well as affected synovial tissue. Large amounts of extracellular gamma3-chains were deposited in the synovial membrane. In addition, marked inflammatory changes with synovial cell hyperplasia were seen. Whether the present case represents primarily a gamma heavy chain deposition disease with reactive inflammatory changes in the joints, or another example of gamma heavy chain disease preceded by seronegative rheumatoid arthritis, remains elusive. Regardless, a possible pathogenic link between the two disease processes is an intriguing possibility.

IgA rheumatoid factor in primary Sjögren's syndrome

Objective: To assess the serum level of immunoglobulin A rheumatoid factor (IgA‐RF) in patients with primary Sjögrens syndrome (pSS) and study the association with immunological and clinical factors. Methods: Sera from 97 pSS patients diagnosed according to the preliminary European criteria and 100 controls were analysed for IgA‐RF in a cross‐sectional study design. Results: IgA‐RF was detected in serum of 25.8% of the pSS patients and in 1% of the controls. In patients with positive vs. negative IgA‐RF, the focus scores in biopsy of the minor salivary glands were 4.41 and 1.43 (p<0.0001), respectively. There was a correlation between positive IgA‐RF and positive antinuclear antibodies (ANA) (r = 0.263, p<0.009), IgM‐RF (r = 0.70, p<0.0001), anti‐SSA/SSB (r = 0.73, p<0.0001), and a high serum level of IgG (r = 0.59, p<0.0001). The presence of renal disease was higher in IgA‐RF‐positive vs. negative pSS patients (20.0% vs. 5.6%, p = 0.047). The serum level of the hormone prolactin (PRL) correlated to the serum level of IgA‐RF (r = 0.31, p = 0.026). Conclusions: The presence of IgA‐RF in patients with pSS is closely associated with the presence of autoantibodies, and with focus scoring in biopsies of the salivary glands. IgA‐RF is associated with renal disease in pSS but we found no correlation to other extraglandular manifestations.

Laboratory Findings in Patients with Psoriasis, with Special Reference to Immunological Parameters, Associations with Arthropathy and Sacro-Iliitis

Twenty-five male and 25 female consecutive patients hospitalized because of psoriasis were examined. The clinical and radiographical findings are presented in detail elsewhere. Increased serum IgA, C3, C4, and C3PA concentrations were found in patients both with and without arthropathy and/or sacro-iliitis. Increased IgG concentrations were found in patients without arthropathy, and of C1 inhibitor concentrations in patients with arthropathy and/or sacro-iliitis. IgG and IgA concentrations were lower in patients with arthropathy than in those without, the difference being most significant in patients with arthropathy of large joints. An association was found between increased C4 concentration and sacro-iliitis, increased CRP concentration and sacro-iliitis and increased C3 concentration and phalangeal joint arthropathy. C4 and CRP concentrations were not associated. A close association between CRP and SAA was observed. Our results indicate that psoriatic arthropathy is not a single uniform joint disease, but represents different forms of arthropathy.

IgG and IgA Subclass Distribution of Total Immunoglobulin and Rheumatoid Factors in Rheumatoid Tissue Plasma Cells

The subclass distribution of IgG and IgA plasma cells, and in IgG and IgA rheumatoid factor (RF) producing cells was studied in sections of synovial tissue from seropositive RA and various types of seronegative arthritis, including ankylosing spondylitis, psoriatic arthritis, and Reiters syndrome. The study was performed with immunofluorescence technique and monoclonal IgG and IgA subclass specific antibodies. IgG RF producing cells were identified by their ability to bind and activate factors both in the early (C3) and late (C5b-9) part of the complement cascade. IgA RF cells were identified by double staining experiments with heat-aggregated IgG and monoclonal antibodies to IgA subclasses. In 23 tissues tested for total IgG, IgG1 cells were usually predominant, while the frequency of IgG3 cells was usually higher than that of IgG2. In 19 tissues also tested for IgA, both IgA subclasses were present in all tissues. IgA1 plasma cells were always predominant, with a mean ratio of IgA1 to IgA2 cells of approximately 10. In the 13 tissues tested for RF-producing cells, the highest frequency of IgG RF cells was found among the IgG3 cells, followed by IgG1 and IgG2. IgA RF cells were found in only one case, all cells being IgA1.

Nonspecific Capillary Proliferation and Vasculopathy Indicate Skin Hypoxia in Erythromelalgia

OBJECTIVE To report on the histopathologic findings of affected skin in consecutively collected biopsy specimens from 49 patients with erythromelalgia (EM). DESIGN Skin biopsy specimens were obtained from the foot arch and analyzed by light microscopy, immunofluorescence microscopy, and electron microscopy. SETTING Oslo University Hospital-Gaustad, University of Oslo, Oslo, Norway. PARTICIPANTS Thirty-one patients had primary EM, 17 patients had secondary EM, and 1 patient had erythromelalgic syndrome. MAIN OUTCOME MEASURE Evidence of microvascular abnormalities in skin biopsy specimens. RESULTS Light microscopy showed evidence of capillary proliferation in 10 of 31 patients with primary EM and in 1 of 17 patients with secondary EM. The biopsy specimen from the patient with erythromelalgic syndrome showed numerous capillary nests with endothelial cell defects and a slight perivascular inflammatory reaction. Among the 17 secondary EM cases, sparse perivascular lymphocyte infiltrations were observed in the biopsy specimens from 2 patients with chronic myelogenous leukemia and 1 patient with diabetes mellitus. Eleven patients also had signs of vasculopathy based on findings of immunodeposits of C3 and fibrin. Six of 30 patients with primary EM showed endothelial abnormalities on electron microscopy. All 3 investigations showed unremarkable biopsy results in 16 cases. CONCLUSIONS Histopathologic analysis is not useful as a routine diagnostic tool in EM because no morphological changes are specific to EM. The capillary proliferation and vasculopathy are assumed to be a consequence of intermittent skin hypoxia (vascular hypothesis of pathogenesis). Whether the proliferation is a consequence of EM or a pathogenic factor in the development of the disease is uncertain.

Adhesion molecule expression and complement activation in vessel walls in synovial tissue from patients with chronic inflammatory joint disease

SummaryHistopathology demonstrating a manifest vasculitis is a rare event in synovial tissue (ST) from patients with chronic inflammatory joint disease. As a possibly more subtle sign of a vasculitic process, complement activation in vessels in ST was studied. In the same tissues, the expression of the adhesion molecules ICAM-1 and E-selectin in vessel walls was examined, to see if the expression was related to vasculitic processes. The study was performed by use of direct immunofluorescence technique on cryostat sections of ST, using mouse monoclonal antibodies to the terminal complement complex (TCC, C5b-9), ICAM-1 and E-selectin. Expression of ICAM-1 was found in the vessel walls in all of 28 tissues tested, whereas E-selectin was found in 4 cases and TCC in 11. E-selectin and TCC were found together in only 1 tissue. The study supports the view that ICAM-1 is always, or nearly always, present in vessel walls in synovial tissue from patients with chronic inflammatory joint disease. E-selectin and TCC may also be present, but the lack of association between these two proteins suggests that the mechanism leading to a complement mediated vasculitic process is different from that causing expression of E-selectin.