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PubMed1992

HLADR5 and C4BQO high frequency and antinuclear antibodies positivity in patients with 21 hydroxylase deficiency from Campania region.

HLA haplotypes, complement C4 factor and factor B immunochemical concentrations and autoantibodies titer have been studied in six patients with mild congenital adrenal hyperplasia (MC-AH), in two patients with classical congenital adrenal hyperplasia (CCAH) and in their parents. A high frequency of DR5 and C4BQO alleles have been found in MCAH patients. Moreover, C4BQO allele is carried out in three out of four cases associated with DR5. In the two CCAH patients we found a B51 and a B14 allele, the last one usually described in the non classical form of the disease in population of different ethnic origin. Signs of autoimmunity in some patients and parents have been found. C4 null alleles were several-fold more frequent among our patients with respect to the same ethnic control group and the autoantibody positivity could be the result of an altered immune regulation. The presence of a positive correlation between cortisol basal levels and C4 and Bf concentrations in the six MC-AH patients suggests an interrelationship between hormonal factors and immunological findings in this disease. Our finding about HLA antigens not previously described in this syndrome may stimulate more profound studies by genomic and cDNA probes.

17-alpha-Hydroxyprogesterone↗
PubMed1994

Immunological pattern in patients with 21-hydroxylase deficiency.

The aim of this work was to perform an immunological study in six patients with 21 hydroxylase deficiency in mild form (M210HD) and in 2 patients with 21-hydroxylase deficiency in classical form (C210HD) and in their parents, in whom a previous HLA,C4,Bf typing demonstrated high prevalence of DR5 and phenotypic absence of fraction C4B of complement (C4BQO). This study contains the evaluation of C3, IgA, IgG, IgM levels, anticardiolipin antibodies (IgG and IgM) and circulating immunocomplexes. A study of lymphocyte subsets was also performed. Among M210HD 1 patient showed presence of anticardiolipin antibodies both IgM and IgG; this patient had shown antinuclear antibodies in a previous study. Among parents, some subjects showed presence of anticardiolipin antibodies and high levels of circulating immunocomplexes. No alterations in C3 and Ig levels were observed. A reduced percentage of CD4 suppressor-inducer (CD4-SI) (p < 0.05 in M210HD and in parents vs controls) and increased percentage of CD4 helper-inducer (CD4-HI) (p < 0.05 in both groups vs controls) were found. No alterations were evidenced in C210HD patients. Data about association between 21-hydroxylase deficiency and autoimmune diseases are rare. Our results confirm that 210HD could be associated to an unbalancement of immune system function and suggest that non immune genes, like 21-hydroxylase one, may influence the expression of autoimmune diseases at least in presence of peculial extended haplotypes.

Adolescent↗
PubMed2003

Diagnosis and treatment of antibody-mediated kidney allograft rejection.

Evidence of a significant pathogenetic role of donor-reactive antibodies (DRA) in kidney allograft rejection is accumulating. At least, partially owing to the recent discovery of the complement split product C4d as a valuable rejection marker, antibody-mediated rejection (AMR) has regained increasing attention. We review here the value of various diagnostic criteria, including immunohistochemistry (C4d staining), histomorphology and posttransplant serology, for the diagnosis of AMR. Furthermore, the mechanisms underlying alloantibody/complement-mediated allograft injury are discussed in detail. Finally, a thorough discussion of recently proposed "anti-humoral" therapeutic strategies is provided.

Acute Disease↗
PubMed2004

Clearance of C4d deposition after successful treatment of acute humoral rejection in follow-up biopsies: a report of three cases.

Acute humoral rejection (AHR) is currently perceived as an immunological reaction against donor antigens mediated by complement-binding antibodies. C4d, a split product of complement activation and bound to endothelial cells of the peritubular capillaries, is used as a diagnostic marker for AHR. We report on three patients with biopsy-proven acute humoral rejection who were treated initially with plasmapheresis (PS). As two of the patients did not recover renal function, and biopsy showed persistent C4d staining after PS, immunoadsorption (IAS) was additionally performed on them. In all patients, renal function recovered, and follow-up biopsies in two patients showed complete disappearance of C4d, 29 days and 58 days after transplantation and only minimal residual C4d deposits in one patient 48 days after transplantation. We conclude that successful treatment of AHR is followed by complete resolution of serological and histological markers of AHR, displayed by the disappearance of C4d.

Adult↗
PubMed1997

Amyloid P immunoreactivity precedes C4d deposition on extracellular neurofibrillary tangles.

Extracellular neurofibrillary tangles (eNFTs) are the insoluble cytoskeletal debris left behind when neurons with intracellular neurofibrillary tangles (iNFTs) die. Reactive microglia and reactive astrocytes gather around eNFTs. Many inflammatory proteins are deposited in their vicinity, including activated components of the classical complement pathway. Agents which are potential activators of the pathway include beta-amyloid protein (A beta) and amyloid P (AP), since these in vitro activators have been reported to be associated with both senile plaques (SPs) and eNFTs. To investigate the apparent order in which these proteins are deposited, we studied by immunohistochemistry the relative association of AP, A beta, and the classical complement protein C4d with eNFTs in Alzheimer's disease (AD), parkinsonism-dementia complex of Guam (lytico-bodig, LB), and elderly non-demented cases. In normal elderly cases with mild tangle development, most but not all eNFTs were AP positive. Substantially fewer eNFTs were C4d positive, and in two of the three cases no eNFTs were A beta positive. In AD and mild LB cases with more extensive tangle development, a high portion of eNFTs were AP positive, and most of them were C4d positive. Only a few were A beta positive. In severe LB cases, with dense tangle development, almost all eNFTs were AP and C4d positive, and a significant number were also A beta positive. AP seems to be deposited early in eNFT exposure and could therefore be a potential activator of the complement pathway, while A beta deposition occurs relatively late in the process, and is therefore unlikely to be responsible.

Aged↗
PubMed2005

Fatal CNS vasculopathy in a patient with refractory celiac disease and lymph node cavitation.

Celiac disease is an enteropathy occurring in genetically predisposed individuals due to a dietary intolerance to gluten. Patients with celiac disease may develop a neurological disorder of unknown cause, although autoimmune mechanisms are suspected. We report on a 56-year-old man with celiac disease, who became refractory to a gluten-free diet and died of a rapidly progressive encephalopathy. Magnetic resonance imaging indicated focal lesions of the cerebellum and brainstem, and electrodiagnostic studies suggested an axonal neuropathy. Autopsy revealed a flattened small-bowel mucosa with intraepithelial lymphocytosis, a spectrum of degenerative changes of the intra-abdominal and mediastinal lymph nodes, including cavitary degeneration, and splenomegaly. Histologically, the lymph nodes showed pseudocyst formation and lymphocytic vasculitis with fibrinoid necrosis, and sections of the brain exhibited fibrinoid degeneration of small blood vessels, sparse perivascular lymphocytic infiltrates, and perivascular ischemic lesions. Identical T-cell clones were identified in the duodenum, stomach, lymph nodes, and spleen. This patient had an unusual neurological disorder related to a vasculopathy, probably mediated by a circulating neoplastic clone of activated T cells.

Brain Diseases↗
PubMed2005

Portal capillary C4d deposits and increased infiltration by macrophages indicate humorally mediated mechanisms in acute cellular liver allograft rejection.

Almost no data exist concerning the role of antibody-mediated mechanisms in human acute cellular liver allograft rejection (ACR). Therefore, the aim of this study was to determine whether ACR is associated with depositions of complement split products and increased infiltration by B-lymphocytes, plasma cells and macrophages. A total of 35 liver biopsy specimens (ACR n=22, controls n=13) were analyzed by immunohistochemical single and double staining. The average numbers of CD 20(+), CD 38(+) and CD 68(+) cells per portal tract were established while the presence of C4d and C3d deposits was evaluated semiquantitatively. Significantly greater numbers of CD 20(+) (P=0.029) and CD 38(+) (P=0.014) cells were found in the ACR specimens than in the control specimens. Additionally, 50% of patients diagnosed with ACR showed C4d deposits along portal capillaries, which was associated with a significantly increased portal infiltration by macrophages (P=0.007). Taken together these results support the involvement of humorally mediated mechanisms in some cases of ACR.

Acute Disease↗
PubMed2006

C4d deposits mark sites of meniscal tissue disintegration.

Although the frequent occurrence of meniscal degeneration is a well-known fact and its consequences include rupture and even loss of the meniscus, the pathogenetic factors are established insufficiently. Because complement factors and leukocytes are present in synovial fluid, we tried to detect complement deposits and macrophages in menisci, which displayed degenerative changes. We therefore performed a retrospective analysis by immunohistochemical staining of C4d and CD68 in meniscal tissue derived from patients (n=15) who underwent meniscectomy because of meniscal tears and from three autopsy cases (n=3). In this study, focal C4d deposits in the meniscal extracellular matrix in areas of mucoid degeneration or fibrillation were demonstrated for the first time, while no C4d deposits in the avascular zone of menisci without signs of degeneration or injury could be detected. In addition, colocalization of C4d and CD68+ cells was found at sites of meniscal tissue disintegration in five cases. These results represent the first evidence for an involvement of complement and macrophages in meniscal tissue disintegration, indicating a complement mediated reaction at the site of tissue alteration.

Adolescent↗
PubMed1993

Morphological diversities of CD44 positive astrocytes in the cerebral cortex of normal subjects and patients with Alzheimer's disease.

The localization of CD44 was investigated immunohistochemically in postmortem human brain tissue of control subjects and patients with Alzheimer's disease. CD44 is a multifunctional cell surface glycoprotein that serves as a receptor for hyaluronic acid, collagen types I and VI, and mucosal vascular addressin. In gray matter, it was found to be associated with some astrocytes of both protoplasmic and fibrous morphology. These positively stained astrocytes were most frequently observed in association with blood vessels, and had morphologies that were highly comparable to those described with the Golgi technique. Double immunostaining for CD44 and glial fibrillary acidic protein (GFAP) revealed that a significant number of these astrocytes were positive for both antigens. However, GFAP staining was mostly confined to the cell somata and proximal processes, while CD44 staining extended to a rich and extensive array of processes. Occasional CD44 positive cells of spherical morphology with a few thin varicose processes were observed. Their processes formed thick terminations on blood vessels, suggesting that these cells are a special class of astrocyte. In Alzheimer's disease brain, the number of CD44 positive astrocytes increased dramatically. These data suggest that astrocytes have very extensive branching patterns, which are reflected by CD44 staining patterns. CD44 may be an important adhesion molecule for these astrocytic processes.

Adult↗
PubMed1983

Amino acid sequence of a polymorphic segment from fragment C4d of human complement component C4.

The amino acid sequence of a segment of 106 residues of C4d has been determined by automated sequence analysis of fragments obtained by CNBr cleavage and enzymic digestion with trypsin. Polymorphism has been detected at 3 positions. Residues 9 and 12 are either valine and leucine or alanine and arginine, respectively. Residue 102 is either valine or arginine. When comparing the protein sequence with the nucleic, acid sequence [Carroll, M. and Porter, R.R. (1983) Proc. Natl. Acad. Sci. USA 80, in press] alanine or serine are found at position 98. These results may in part help to explain the inherited variants of human C4 seen on gel electrophoresis.

Amino Acid Sequence↗
PubMed1984

Primary sequence differences between Chido and Rodgers variants of tryptic C4d of the human complement system.

Human tryptic C4d of the Chido and Rodgers variant was fragmented by cyanogen bromide and trypsin. The fragments were characterized by amino acid analysis and sequence determination. Polymorphism between the two genetic variants was detected in 5 positions. Four were closely located (residues 141, 142, 145, 146), where Leu, Ser, Ile, His occurred in the Chido variant and Pro, Cys, Leu, Asp in the Rodgers variant, respectively. In position 94 Gly was found in Chido and Asp in Rodgers. Alignment of the fragments was performed and it is concluded that tryptic C4d of both variants contains 346 residues.

Amino Acid Sequence↗
PubMed1990

Prediction of domain organisation and secondary structure of thyroid peroxidase, a human autoantigen involved in destructive thyroiditis.

Organ specific autoimmune diseases are relatively common immunological disorders in man which include thyroid autoimmune disease, insulin-dependent diabetes mellitus and myasthenia gravis. The target autoantigens in some of these diseases have recently been characterised. In thyroid autoimmune disease this includes the key enzyme, thyroid peroxidase (TPO), which is involved in the generation of thyroid hormone. Structural knowledge about autoantigens such as thyroid peroxidase will allow a greater understanding of the interaction between autoantigens and the aberrant immune response, and facilitate the development of strategies for antigen-specific therapeutic manipulation. We report here a prediction of the secondary structure of thyroid peroxidase, together with the results of circular dichroic spectroscopy of a homologous purified enzyme. A combination of 3 secondary structure prediction programs has been used, following multiple sequence alignment, and TPO has been found to consist mainly of alpha-helical conformation, with little beta-sheet present. This structure prediction, together with knowledge of the exon-intron boundaries allows a model for the domain organisation of the TPO molecule to be proposed.

Amino Acid Sequence↗
PubMed1989

Activation of the complement system in primary sclerosing cholangitis.

Recent evidence, including the presence of circulating immune complexes, suggests that abnormalities of humoral immunity may be important in the pathogenesis of primary sclerosing cholangitis. The aim of the present study was to determine whether activation of the complement system is present in patients with this disease, as this would be supportive evidence of a role for circulating immune complexes in primary sclerosing cholangitis. Plasma complement fragments C3d and C4d, and serum C3 and C4, their respective parent molecules, have been assayed. Both C3d and C4d were elevated in patients with primary sclerosing cholangitis compared with patients with extrahepatic obstructive cholestasis and normal controls (p less than 0.01 in all instances). C3 was elevated in both patient groups, in whom it was similar, compared with normal controls (p less than 0.001 in both cases), whereas C4 was similar in all groups. Elevated levels of circulating immune complexes were identified in 21 of 24 (88%) patients with primary sclerosing cholangitis, but in none of the normal controls. These findings support the hypothesis that in primary sclerosing cholangitis circulating immune complexes are associated with activation of complement via the classical pathway.

Adult↗
PubMed1984

Quantitation of human protein S in the plasma of normal and warfarin-treated individuals by radioimmunoassay.

Protein S was purified from human plasma and used to raise monospecific antibodies. A double antibody equilibrium radioimmunoassay was constructed and met all the requirements for a sensitive, accurate and specific determination of Protein S. The sensitivity of the assay was between 8-250 ng of Protein S/ml and the coefficient of variation was 2-6% within assays and 13-19% between assays. Complement C4b-binding protein or Protein C did not effect the measurement of Protein S. Complete competition with parallel slopes of inhibition was seen among purified Protein S and plasma from normal and warfarin-treated individuals indicating immunochemical identity and validating the measurement of Protein S in plasma. The concentration of Protein S in normal plasma (n=24) was 23.4 +/- 4.42. micrograms/ml and in plasma from warfarin-treated individuals (n=24) was 12.6 +/- 3.92 micrograms/ml. Thus, a common feature of individuals undergoing warfarin therapy is the reduction of approximately 50% in the concentration of each of the vitamin K-dependent proteins.

Antibodies, Monoclonal↗
PubMed1988

Plasma protein S activity measured using Protac, a snake venom derived activator of protein C.

Functional activity of protein S, a cofactor of activated protein C-dependent inhibition of blood coagulation, in human plasma was measured by using Protac, a snake venom derived activator of protein C. This assay appeared to be specific for protein S, because 1) the activated partial thromboplastin time of protein S-depleted plasma depended on the purified protein S added in the presence of Protac; and 2) the level of protein C in plasma sample (0 to 10 micrograms/ml) had no influence on the clotting time. The cofactor activity of protein S in the plasma of normal men (n = 16) and women (n = 14) was 99.4 +/- 23.8% and 98.6 +/- 24.5% respectively. The protein S activity in the plasma of pregnant women at pre- and post-partum (n = 14), and that in the plasma of patients under warfarin therapy (n = 20) were 46.2 +/- 18.9%, 45.8 +/- 19.6% and 24.0 +/- 15.7%, respectively. In these plasmas, the levels of protein S activity were lower than those of total protein S antigen, but were similar to those of free protein S antigen. In 16 patients out of two families with congenital protein S deficiency, the protein S activity, the free antigen and the total antigen were 9.4 +/- 6.9%, 13.3 +/- 4.6% and 57.4 +/- 20.7%, respectively. There was no significant relationship between the level of protein S activity and that of a complemental C4b-binding protein antigen in any of these patients.

Female↗