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PubMed1984

Inherited complement deficiencies.

Isolated genetic deficiencies of individual components of the complementary system have been described in man for all the components of the classical pathway and the membrane attack complex as well as for Factor I, Factor H and properdin. It is only for Factor B and Factor D of the alternative pathway that homozygous deficiency states are not so far known. Complement deficiency states provide the most direct way of looking at the role of the complement system in vivo and emphasize the importance of complement in resistance to bacterial infection and in particular to infection with Neisseria. This association is not unexpected since in vitro studies have shown complement to be an efficient enhancer of phagocytosis and inflammation. The particularly frequent occurrence of neisserial infection may be ascribed to the ability of these organisms to survive in phagocytic cells so that the plasma cytolytic activity provided by complement is needed to kill them. On the other hand the strong association between complement deficiencies and immune-complex diseases--especially systemic lupus erythematosus--was unexpected and seems paradoxical in view of the large part played by complement in the pathogenesis of immune complex mediated tissue damage. The paradox can be explained in part by the necessity for an intact complement system in the solubilization and the proper handling of immune complexes. It is also likely that complement deficiency can allow the persistence of low virulence organisms that produce disease solely by an immune complex mechanism. Recently described deficiencies of complement receptors and their effects in vivo are described.

Blood Donors↗
PubMed2003

Cloning and expression of the complement receptor glycoprotein C from Herpesvirus simiae (herpes B virus): protection from complement-mediated cell lysis.

Simian herpes B virus (SHBV) is the herpes simplex virus (HSV) homologue for the species MACACA: Unlike in its natural host, and unlike other animal herpesviruses, SHBV causes high mortality in accidentally infected humans. SHBV-infected cells, like those infected with HSV-1 and equine herpesvirus types 1 and 4, express complement C3 receptor activity. To study immunoregulatory functions involved in susceptibility/resistance against interspecies transmission, the SHBV glycoprotein C (gC(SHBV)) gene (encoding 467 aa) was isolated. Sequence analysis revealed amino acid identity with gC proteins from HSV-2 (46.9 %), HSV-1 (44.5 %) and pseudorabies virus (21.2 %). Highly conserved cysteine residues were also noted. Similar to gC(HSV-2), gC(SHBV) is less glycosylated than gC(HSV-1), resulting in a molecular mass of 65 kDa if expressed in replication-deficient vaccinia virus Ankara. Stable transfectants expressing full-length gC(SHBV) on the cell surface induced C3 receptor activity and were substantially protected from complement-mediated lysis; no protection was observed with control constructs. This suggests that expression of the gC homologues on infected cell surfaces might also contribute to the survival of infected cells in addition to decreased virion inactivation. Interestingly, soluble gC(SHBV) isolated from protein-free culture supernatants did not interfere with the binding of the alternative complement pathway activator properdin to C3b, which is similar to our findings with gC(HSV-2) and could be attributed to major differences in the amino-terminal portion of the protein with extended deletions in both gC(SHBV) and gC(HSV-2). Binding of recombinant gC(SHBV) to polysulphates was observed. This, together with the heparin-sensitivity of the gC(SHBV)-C3 interaction on the infected cell surface, suggests a role in adherence to heparan sulphate, similar to the gC proteins of other herpesviruses.

Amino Acid Sequence↗
PubMed1977

Immunopathology of cicatricial pemphigoid: studies of complement deposition.

Immunopathologic investigations were conducted on the sera and oral mucosal tissue specimens of 23 patients with cicatricial pemphigoid. A linear, continuous basement membrane zone pattern was noted in 83% of oral mucosal biopsy specimens studied. This pattern is indistinguishable from the pattern noted in immunofluorescence studies of bullous pemphigoid, herpes gestationis, and some cases of desquamative gingivitis. Complement studies provided data supportive of classical pathway activation in cicatricial pemphigoid tissue. Deposition of IgA with Factor B, properdin, and C3 raised the possibility of alternative pathway activation, a question requiring further study. Circulating antibasement membrane zone antibodies were noted in the sera of two patients with cicatricial pemphigoid.

Basement Membrane↗
PubMed1980

Analysis of immunological responses in psoriatic lesions: (1) immunopathological studies on psoriatic lesions.

In order to understand immunological responses in psoriatic lesions, immunofluorescent findings have been compared in early psoriatic lesions and fully developed plaque lesions. IgG and IgA were detected as the main antibodies in the horny layer by immunohistology. The IgA at the site of leukocyte accumulation in the horny layer seemed to be associated with secretory component (S-component) and joining chian. Regarding complement, the alternate pathway might be related to the immune reaction as the initial response, because deposits of C3, properdin and glycine rich beta-glycoprotein were found more frequently than C1q-deposit in the both lesions. In the dermis S-component was also detected at the dermal papillae adjacent to the dermoepidermal (D-E) junction of the lesions and no deposit of S-component was observed in uninvolved skin of psoriatic patients. This, however, is not a specific pattern in psoriatic lesions since deposits of S-component were found at the dermal papillae and D-E junction in other dermatoses. These findings might suggest that the immunological response was initiated by secretory IgA in horny layer, which was composed of dimeric IgA and S-component at the D-E junction and which passed easily through the epidermal cells.

Adolescent↗
PubMed1979

Autosensitization to DNA: evidence for an immunologic basis.

A 59-year-old female with spontaneous painful ecchymoses developed ecchymoses after intracutaneous injection of washed autologous whole blood cells and calf thymus DNA. Immunofluorescent studies of the spontaneous lesions revealed granular deposits of IgM, C3, factor B and properdin at the dermal-epidermal junction but no deposits in her normal skin. T cells were decreased in number but responded normally to polyclonal mitogens and did not transform in response to DNA containing antigens. Repair of UV-damaged DNA by her lymphocytes appeared to be depressed. The findings presented here are the first immunologic abnormalities uncovered in this disorder and may help in understanding the pathogenesis of the inflammatory lesions seen in autosensitization to DNA.

Autoantibodies↗
PubMed1978

Weber--Christian syndrome in infancy.

A review of Weber-Christian syndrome in infancy is presented along with the report of two cases. Both infants had low serum properdin levels, and one patient showed remissions of his disease when he was T-lymphocytopenic. This suggests that the T-lymphocyte may have an important role in the pathogenesis of Weber--Christian syndrome.

Adipose Tissue↗
PubMed1980

Epidermolysis bullosa acquisita. Immunofluorescence, electron microscopic and immunoelectron microscopic studies in four patients.

Four patients with the clinical picture of epidermolysis bullosa acquisita were investigated. Biopsies were taken from the involved and uninvolved areas of the skin and the immunohistochemical and microscopic changes were studied. Direct immunofluorescence showed deposition of IgG and C3/4 in a linear or norched pattern along the epidermal basement membrane in both the involved and the uninvolved skin. In addition IgA (3/4), IgM (1/4), C4 (3/4) and properdin (3/4) could be detected. Indirect immunofluorescence revealed the presence of circulating antibodies against inter alia the epithelial basement membrane zone in one patient. Routine electron microscopy showed that the blister was situated in the dermis leaving the basal lamina in the roof of the blister. With immunoelectron microscopy using peroxidase-labelled antibody the in vivo deposition of IgG was observed just beneath the basal lamina in the dermis of both the perilesional and the uninvolved skin. These observations show that epidermolysis bullosa acquisita is a distinct entity, in which autoimmune mechanisms might possibly play a role.

Adult↗
PubMed1985

A direct immunofluorescence study in elastosis perforans serpiginosa.

Two cases of elastosis perforans serpiginosa were studied by direct immunofluorescence. In one case, homogeneous deposits of IgM, C3 and C4 on the abnormal elastic fibres in the papillary dermis were demonstrated. In addition, in both cases, along the basement membrane zone, coarse linear deposits of fibrinogen and properdin were observed inside and near the transepidermal channels. Groups of cytoid bodies stained for IgM and occasional weak linear deposits of IgG, IgA, IgM and C3 were also observed. The immune deposits on the abnormal elastic fibres might indicate antigenic alteration and activation of humoral immunological mechanisms in the process of their elimination. The other findings may reflect a non-specific binding by damaged tissue structures.

Adolescent↗
PubMed1990

The level of mannan-binding protein regulates the binding of complement-derived opsonins to mannan and zymosan at low serum concentrations.

When sera diluted to 5% in a buffer containing calcium and magnesium were incubated with mannan-coated ELISA plates, C4 fragments, properdin and factor B were bound to the plates as well as the expected opsonic C3 fragments, C3b and C3bi. The calcium-dependent lectin mannan-binding protein, which is structurally similar to C1q, was also shown to bind in this assay and analysis of sera from 179 healthy blood donors revealed that the binding levels of all these proteins were highly significantly correlated. Results obtained with a previously described C3b opsonic assay using zymosan also correlated with the mannan-binding levels. When the sera were diluted to 5% in the presence of Mg-EGTA there was no detectable binding of complement proteins to the mannan surface, confirming that no alternative pathway activation occurred at this serum concentration. When sera were diluted to 5% in a buffer containing EDTA in order to study immunoglobulin binding in the absence of complement activation, the levels of bound IgG1, IgG2, IgG3, IgA and IgM antibodies were found to be completely unrelated to the C3bi binding levels previously observed. The results suggest that in this experimental system using low concentrations of serum, mannan-binding protein initiates an antibody-independent mechanism of cleavage of the classical pathway component C4, which subsequently regulates the degree of cleavage of C3 and recruitment of alternative pathway proteins.

Carrier Proteins↗
PubMed1993

Clustering of neutrophil leucocytes in serum: possible role of C1q-containing immune complexes.

Clustering activity for neutrophil granulocytes was generated in pooled normal human serum (NHS) by incubation of the serum with preformed IgG aggregates, but not in heat-treated NHS (56 degrees C, 30 min), indicating that the function was complement-dependent. Judging from results of experiments with complement-deficient sera, and serum depleted of C1q, factor D and properdin, recruitment of the complement system beyond C1 was not required for induction of the activity. Zymosan treatment of NHS resulted in some neutrophil clustering activity, but recombinant C5a had a limited effect. C1q added to heat-treated NHS in conjunction with performed IgG aggregates supported neutrophil clustering in a dose-dependent manner. The serum C1q inhibitor, a chondroitin 4-sulphate proteoglycan known to interact with the collagenous part of C1q, clearly reduced neutrophil clustering in heat-treated NHS supplemented with C1q and IgG aggregates. The C1q inhibitor also reduced the inherent neutrophil clustering activity of some sera from patients with systemic lupus erythematosus (SLE). Neutrophil clustering activity in SLE serum was earlier shown to be inversely related to the number of circulating neutrophils in vivo. Although the precise mechanisms remain unclear, we propose that C1q-containing immunoglobulin complexes mediate neutrophil clustering through C1q receptors, and that this might contribute to pathogenesis of immune complex diseases such as SLE.

Antigen-Antibody Complex↗
PubMed1994

HLA associations with inclusion body myositis.

Inclusion body myositis (IBM) is defined clinically by a characteristic pattern of progressive proximal and distal limb muscle weakness and resistance to steroid therapy, and histologically by the presence of distinctive rimmed vacuoles and filamentous inclusions as well as a mononuclear infiltrate in which CD8+ T cells are predominant. Muscle damage is believed to be mediated by autoimmune mechanisms, but very little information is available on the immunogenic features of IBM. MHC class I and DR antigens were typed on 13 caucasoid patients with IBM using standard serological techniques or by allele-specific oligonucleotide typing. Complement components C4 and properdin factor B (Bf) were typed by immunofixation after electrophoresis. Restriction fragment length polymorphisms (RFLP) in the class III region were analysed using cDNA probes for C4 and 21-hydroxylase (CYP21) after Taq 1 digestion. IBM was associated with DR3 (92%), DR52 (100%) and HLA B8 (75%). The phenotype data were examined for likely haplotypes by considering together the alleles at the class I, DR and complement loci along with the C4 and CYP21 RFLP. Ten of the DR3+ subjects had a 6.4-kb C4-hybridizing fragment characteristic of a deletion of C4A and CYP21-A. These patients probably carried all, or at least the class II and III regions, of the extended haplotype marked by B8/C4A*Q0/C4B1/BfS/DR3/DR52, which has been associated with several autoimmune diseases and is present in 11% of the healthy caucasoid population. Of the remaining subjects, two had evidence of the extended haplotype marked by B18/C4A3/C4BW*0/BfF1/DR3, which is present in less than 5% of the healthy population and has been associated with insulin-dependent diabetes mellitus. These data provide support for an autoimmune etiology for, and genetic predisposition to, IBM.

Adult↗
PubMed1984

Clinical and immunopathologic study of mesangial IgM nephropathy: report of 41 cases.

Forty-one out of 408 cases (or 10%) of primary glomerular disease had diffuse fine granular to arc-like short linear mesangial deposits of IgM by direct immunofluorescence. The IgM deposition was accompanied by C1q and/or C4 in the same locality in 29 cases, by C3 in 10, and by trace amounts of IgA in 6. Properdin-factor B was not detected. Fine granular electron dense deposits of low density were detected in the mesangium in all 41 cases by electron microscopy, usually as a discrete granular or arc-like pattern beneath the mesangial glomerular basement membrane and correlated well with the immunofluorescence findings. An immune complex disease with complement activation via the classical pathway is suggested. The ages of the patients varied from 2 to 58 years (average 23.8 years). A male predominance of 2.2:1 was identified. Serum IgM level was elevated in 46.7% of the cases. The majority (87.8%) of the cases manifested a nephrotic syndrome or relapse at time of biopsy, and the remaining cases experienced persistent or intermittent proteinuria. Among the 36 nephrotic patients, 22 cases (61.1%) demonstrated complete remission with steroid therapy, 9 cases (25%) were resistant, and 5 cases (13.9%) had partial remission. Complete and partial remissions were later achieved with cytotoxic drugs or methylprednisolone pulse therapy in 3 and 4 cases respectively in the steroid resistant patients. Frequent relapses occurred during the course in 22 out of 32 cases (68.8%) who had experienced complete or partial remission. Follow-up study after biopsy demonstrated that sustained complete remission was achieved with prednisolone with or without cytotoxic drugs and pulse therapy in only 14 (42.4%) of the 33 nephrotic cases who had been followed up for longer than 6 months, and six of them had had previous relapses. Pathologically, 56.1% of the patients showed mild to moderate increase in mesangial matrix and cellularity. Focal and segmental sclerosis was demonstrated in four cases (9.8%). However, minimal glomerular change was also common (34.1%). The patients with minimal change seemed to have a higher complete remission rate than patients with more evident glomerular alterations, although the difference was not statistically significant. This clinical and immunopathological study suggests that mesangial IgM nephropathy is an important disease in Taiwan, with a variable response to treatment and frequent relapses.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1989

Hereditary, complete deficiency of complement factor H associated with recurrent meningococcal disease.

Complement factor H (beta-1H globulin) is an important regulatory protein which inhibits the spontaneous complement activation via the alternative pathway. We describe a 15-year-old girl without any detectable factor H in plasma. She has had two episodes of meningococcal disease, but is otherwise completely healthy. Secondary to the factor-H deficiency, the levels of factor B, properdin, C3, and C5-C9 were strongly reduced due to spontaneous in vivo activation of the alternative complement pathway. Plasma C3dg was strongly elevated in spite of the factor-H deficiency; apparently erythrocyte CR1 substitutes for factor H in C3 degradation. Neither C3 nor complement lesions were demonstrable on her erythrocytes which did, however, show increased, spontaneous haemolysis in vitro in citrate plasma, but not in serum. The patient is a single child and her parents, who are unrelated and healthy, had half-normal levels of factor H. This reduction of factor H is sufficient to cause increased, spontaneous activation of the alternative pathway.

Antibodies, Bacterial↗
PubMed1979

Strong linkage disequilibrium between HLA-Dw2 and and BfS in multiple sclerosis and in the normal population.

An increased frequency of the S allele of Properdin factor B (BfS) was found amongst 162 patients with multiple sclerosis (MS) compared with 470 normal controls. This increase was shown to be due to a strong linkage disequilibrium (LD) between BfS and HLA-Dw2 in 77 patients typed for both systems (delta = 3.84%, P = .0002). The same LD was demonstrated amongst 100 normal controls (delta = 2.24%, P = .0049) and 31 patients with idiopathic demyelination of the peripheral nervous system (IDPN). A total of 70 haplotypes with HLA-Dw2 were encountered (40 MS, seven IDPN and 23 normal controls) and all contained BfS. In the MS patient group, a much weaker association was noted between BfS and HLA-B7 suggesting either that the Bf locus is musch closer to the HLA-D than the HLA-B locus or (and) that HLA-D and Bf products selectively interact (perhaps on the surface of B lymphocytes) with evolutionary advantage or disadvantage resulting from certain allelic combinations. Strong associations between BfS1 and HLA-Bw21 (P = .0000) and BfF1 and HLA-B18 (P = .0001), both previously reported, were confirmed in the current study. No increase in the frequency of a glyoxalase (GLO) allele was found amongst the MS patients and no LD was encountered between HLA-Dw2 and a GLO allele. The possibility that the HLA-Dw2, BfS disequilibrium has resulted from a selective advantage conferred on the general community but at the expense of increasing susceptibility to MS should be considered.

Chromosome Mapping↗
PubMed1979

Definition of two LD antigens in rhesus monkeys.

Two rhesus (Macaca mulatta) monkey lymphocyte-defined (LD) antigens have been identified using two typing cells as stiumlators in a one-way mixed leukocyte culture (MLC) assay. An analysis of the genetic behavior of these LD antigens in six rhesus monkey families revealed that both antigens were linked with RhLA. One probable recombinant indicated that the LD locus lies outside the two known RhLA-SD loci and the locus which controls the serum protein, properdin B(Bf). These two antigens, LD1 and LD2, had observed gene frequencies of 0.07 and 0.25, respectively. Neither of these two new LD antigens was significantly associated with any serologically defined (SD) antigen.

Animals↗
PubMed1981

Studies on an isolated West Indies population: I. Analysis of HLA genotypes.

The transmission of HLA genes was studied in an isolated population of French origin on the lesser Antilles islands in the West Indies. The study of 74 unrelated individuals, 44 of whom were genotyped, was carried out for the alleles of HLA loci: A, B, C and Bf (proactivator factor of properdin). As a result of the founder effect and the inbreeding process, the HLA haplotypes were noted to be less polymorphic than in a French continental population. Two haplotypes: A2, Cw5, B12, BfS and A3, C-, B14, BfF represent 24% of the observed haplotypes, and only 2% of the reference haplotypes in France. No significant excess or deficit of homozygotes was observed at the A and B loci.

Deafness↗
PubMed1983

HLA antigens and Bf allotypes in lichen sclerosus et atrophicus.

A study of the HLA-A, B and DR antigens and properdin factor B allotypes of 26 patients with lichen sclerosus et atrophicus and a normal control population showed an increase in the HLA-Aw31 antigen only. However, when the HLA-A and B frequencies were combined with the results of a previous independent study a significant increase in both HLA-Aw31 and HLA-B40 was noted. These findings suggest an association between lichen sclerosus et atrophicus and the HLA system.

Complement Factor B↗
PubMed1983

Intra HLA-D/DR region recombinant detected by primed lymphocyte typing (PLT).

The chromosome 6 markers, HLA-ABC, D, DR, MT, properdin factor Bf, and complement factors 2 (C2) and 5 (C4), were studied in three families, each of which included two HLA identical siblings, one or both of whom were known to be HLA-B: GLO recombinants. The families were also typed with primed lymphocyte typing (PLT) for HLA-D/DR region associated DP antigens. None of these studies gave evidence that the recombinations had occurred within the HLA region. Mixed leucocyte culture (MLC) tests within the families showed no detectable stimulation between the HLA identical siblings in two of the families, but a very weak stimulation between the HLA identical siblings (H and G) in the third family (GG). No reactive PLT reagents were generated when cells from the HLA identical siblings of the first two families were primed against each other. In contrast, priming between cells of H and G gave rise to reactive reagents. One of these (GHx), reacted with a determinant which segregated within the GG family as if child G was a paternal recombinant between the HLA-D, DR, DP, and C4 loci, on the one hand, and on the other hand one or more loci governing other HLA-D/DR region controlled lymphocyte activating determinants. This reagent was only restimulated by cells from two of 47 unrelated individuals. The other PLT reagent (HGx) did not give a clearcut pattern within the family because it was weakly positive with all family members (most of whom were D/DR2-positive) except the specific responder; in the panel it reacted with a determinant significantly associated with D/DR/DP2. Other PLT reagents could be generated within the family against lymphocyte activating determinants controlled by genes in the two paternal haplotypes telomeric to the assumed recombinational site. These reagents gave stronger reactions than the HGx and GHx reagents and reacted with two determinants in the unrelated panel strongly associated with D/DR/DP2 and D/DR/DP6, respectively. It seems likely that the GG family represents a third example of a recombination between the HLA-DR and SB loci. Our findings further support the assumption that the DR determinants may be immunodominant in lymphocyte activation.

Chromosomes, Human, 6-12 and X↗