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The highly polymorphic fourth component of human complement (C4) is usually encoded by two genes, C4A and C4B, adjacent to the 21-hydroxylase (21-OH) genes, and is also remarkable by the high frequency of the null alleles, C4A*Q0 and C4B*Q0. Despite considerable structural homology, the gene products of the two loci differ in hemolytic activities, antigenic reactivities and covalent binding affinities to antigens and antibodies. Complete C4 deficiency is exceptional because this condition appears only in homozygotes for the very rare double-null haplotype C4AQ0,BQ0. In contrast, partial C4 deficiency is a common immune protein defect in all human populations as a consequence of the high frequency of the C4 half-null haplotypes. Complete C4 deficiency in most cases gives rise to SLE and an increased susceptibility to infections, and partial C4 deficiencies predispose to different auto-immune diseases related to extended HLA haplotypes bearing the C4 half-null haplotypes. Studies at the DNA level have shown that about half of the null alleles are due to deletions involving C4A and 21-OHA, C4B and 21-OHA or C4B and 21-OHB. Larger deletions including both C4A and C4B genes have never been observed. Partial C4 deficiency may be observed in combination with other complement deficiencies or immune defects, and allo- or auto-anti-C4 immunization is also a possible consequence of this genetic abnormality. Although the pathogenesis of the diseases related to complete and partial C4 deficiencies is not yet clearly understood, it is evident that C4 null alleles represent interesting markers and additive risk factors for autoimmune phenomena.

We report an H deficiency in two Algerian brothers who had early-onset glomerulonephritis. In addition, one suffered from serious lung infections. The H deficiency was defined by undetectable CH50 and AP50, and low levels of H, C3 and B (less than 10% of normal levels). I and classical pathway components, including C4-bp were normal. CR1 was present on both patients' erythrocytes. No nephritic factor or other circulating alternative pathway activator was detected. The parents, who are first cousins, and a healthy brother and sister had half-normal levels of H. These findings favor an autosomal recessive transmission of the H defect. Although by electron microscopy renal biopsies from both patients were typical for dense intramembranous deposit disease, immunofluorescence microscopy showed an atypical pattern with abundant granular C3 deposits within the mesangium and along the capillary walls. Alternative pathway activators, possibly related to dense deposits, may allow the formation of membrane-associated C3/C5 convertases, unusually stable in the absence of H, since C5, C6, C7, C8 and C9 levels were decreased in both patients. This observation may represent an interesting clue to the relationship between nephritic factor, alternative pathway activation, and dense intramembranous deposit disease.

325 HLA-A, B and Bf haplotypes obtained from family studies were investigated. In addition, 216 of these were tested for HLA-Cw2, Cw4, Cw5. Four different statistical methods were employed to study 2, 3 or 4 loci gametic associations in order to compare the results obtained by these different methods. Our results were then compared with those of other authors who employed similar methods. Piazza's method, used to identify gametic associations, was not able to show any 3 loci associations in our material. The Delta Standard Method employed in conjunction with Factorial Correspondence Analysis was found suitable for the study of chromosomal prevalence in a population.

A comparison of the frequency of HLA-A, B, C and Bf antigens observed in a group of 75 chronic schizophrenics and in a control group of 184, all strictly from Alsace, does not carry any argument in favour of a strong genetic association between schizophrenia and the antigens studied. In effect, the modifications observed in the schizophrenic sample--decrease in the frequency of A10 and B5 antigens, and increase of A29 and BfF--are not statistically significant when the probabilities are multiplied by the number of tested antigens. These preliminary results however do not permit to exclude the possibility of an association between schizophrenia and the tested antigens.

The haplotypic frequencies of the fourth component of complement (C4) and factor B (Bf) have been determined in 44 Alsatian type 1 diabetics. An increased frequency of the rare allele Bf F1 (9.1% vs 1.5%) and of the silent alleles of C4 (C4 AQO: 21.6% vers 15.5% -C4 BQO: 29.6% vs 16.0%) was observed in diabetics in comparison to the general population of the same geographic area. A complete HLA haplotype determination has been obtained in 24 type 1 French diabetics. Three haplotypes were associated with the diabetic susceptibility: HLA-A30 CW5 B18 BfF1 C4A3BQO DR3 (18.75% vs 0.86%), HLA-A1 CW7 B8 BfS C4AQOB1 DR3 (15.58% vs 4.17%), HLA-A2 CW3 BW62 BfS C4A3B3 DR4 (6.25% vs 0.45%). The authors suggest that the silent alleles of C4 could modulate the expression of the diabetic susceptibility genes by lowering of the serum C4 hemolytic activity.

Thirteen patients (2 children and 11 adults) with idiopathic thrombocytopenic purpura were treated with high doses of human immunoglobulins intravenously (0.4 g/kg bodyweight/day for 5 days). The platelet count rose sharply in 11 patients, with considerable individual variations in terms of maximum count achieved and delay as well as duration of response. Only two adult patients refractory to previous treatments failed to show any significant response. Complete correction of platelet counts was observed in the two children, whereas most adult patients showed incomplete and transient response. No difference was observed between splenectomized and non splenectomized patients. Survival of 111 Indium-labelled autologous platelets was studied in 2 patients after correction of platelet count and was still found shortened. Circulating immune complexes, when present, were not modified by immunoglobulin infusions. In all patients a significant reduction of the fourth component of serum complement was noted after treatment.

Genetic deficiencies of complement proteins are now more often recognized and analysed more precisely because the structure of the different complement proteins is better known. Partial defects may be detected in some components by the combined utilization of titration techniques, polymorphism studies and linkage analyses. The partial deficiency in C4 seems to be the most frequent protein deficiency in the human. The complement markers on the short arm of the sixth chromosome in man (BF, C2, C4A and C4B) are located in close proximity to the HLA-D/DR region. The combined study of the complement and HLA markers will probably allow the fine structure of the HLA region to be better defined. The association of some diseases with HLA types will probably also be better specified by the definition of associations not only with HLA-B or HLA-D types but also with the BF, C2 and C4 types.

Sera from fourty-six non-congenic adult pigs from one inter-related herd were tested for their haemolytic serum complement levels. A comparison of these data with the major histocompatibility complex (SLA) genotypes of these animals resulted in the demonstration of highly significant differences in lytic activity between sera obtained from animals of two distinct SLA haplotypes. These data showed a high correlation between the SLA complex and the level of haemolytic activity.

A "new" variant band in the Bf system has been found in the serum of three individuals belonging to a tribe of Brazilian Indians (Karaja--Bananal--Goias) and in the serum of a Caucasian individual from the area of Strasbourg. It is highly probable that the band represents another allele at the Bf locus BfS0.8.

An unexpected MLR reaction has been observed between three HLA-identical sibs; it consists of bidirectional positive MLR between identical female twins and a sister. No argument for a lymphoid mosaic could be found, although twins were frequent in the family; similarly no HLA-A/B or HLA-B/D recombinant could be demonstrated. The MLR, although weak, was highly reproducible. PLTs could be raised between the sibs, without an apparent segregation in this family nor in five other families, but such PLTs discriminated well between the positive and negative controls. In the absence of any proof that such a weak MLR locus could be on another chromosome than chromosome 6, two lines of argument are indirect evidences that such a locus could be indeed on chromosome 6: one of the sibs differs from the two others for two markers outside HLA--D--DR--Bf: glyoxalate (GLO) and red blood group P.

The loci for the complement proteins BF and C2 and the two loci for C4 are closely linked to one another, as are the duplicated steroid 21 hydroxylase (21-OHase) genes to the C4A and C4B loci. The alleles of these four loci occur in specific combinations termed "complotypes". We have studied the gene frequencies of their different products in the Lebanese population and compared these values with those found in other populations. We observed a novel complotype (S B 4 6) in one family and a complotype with a so far undescribed variant of the C4A locus. Using several restriction fragment length polymorphisms (RFLPs), we have defined restriction fragment linkage groups. The combined use of C4 and 21-OHase probes allowed us to detect different types of deletions and duplications at these loci in the Lebanese population.

Homozygous typing cells (HTC) for two new HLA-D determinants, EI and RE, defined by family studies, are described. The HLA-D typing experiments among more than 300 unrelated individuals showed phenotype frequencies of 0.045 for EI and 0.098 for RE. Since the tested population was also typed for its HLA-A and -B alleles, linkage disequilibrium parameters could be calculated: HLA-D type EI was statistically significantly associated with HLA-B13 and Bw17, HLA-D type RE with HLA-Bw40. These data support the working hypothesis that both EI and RE are new alleles of the HLA-D series.

We studied 201 unrelated French Basque individuals for HLA and Bf polymorphisms. The haplotypes of eighty-seven of them were deduced from family studies. The results show the frequency of the Bf F1 allele (0.1393) which is the highest one currently reported. They confirm the high frequencies of HLA-Aw19.2 and B18 previously reported in that population and show that a whole haplotype with strong linkage disequilibria, namely Aw19.2, Cw5, B18, Bf F1, DRw3 is frequent. On the other hand, the gene frequency of Bf S is decreased (0.5497) as compared with the other European Caucasoïd populations, while a slight increase in the Bf F gene frequency (0.2960) appears. These results point out that it is of importance to consider the genetic background choosing the population where linkage disequilibria are to be studied.

Three of four children in a family have homozygous (less than 1% of normal) deficiency of factor H of the complement system and both parents, who are first cousins, are heterozygous for the same defect. The father and two of the H-deficient siblings also have a partial C2 deficiency. One of the children with combined deficiencies is affected by systemic lupus erythematosus with nephritis. No increased susceptibility to infections has been observed in the family. H deficiency is inherited in an autosomal codominant manner and is independently transmitted from C2 deficiency and HLA haplotypes. In the homozygous state it is associated with very low serum concentrations of B and C3, barely demonstrable as activated molecules. C5 is greatly reduced (less than 5%). Also, properdin and C6-9 are decreased. The findings in this family demonstrate that the occurrence of systemic lupus erythematosus in one of the children affected by a combined deficiency of factor H and C2 raises the question whether this pathology is related to the complete factor H or to the heterozygous C2 deficiency. Complete H deficiency is not necessarily accompanied by overt illness.

In a case of preleukemic dyserythropoiesis, in vitro red cell lysis tests showed a positive acidified serum test whose characteristics are described. The positive acidified serum test occurred in 10 normal sera, in 1 serum with complete deficiency of the fourth component of complement and in 1 serum with complete deficiency of the second component of complement. The test was found negative with 2 hyperlipemic sera. The other in vitro red-cell lysis tests were negative. The results of the in vitro lysis tests were different from the results obtained in paroxysmal nocturnal hemoglobinuria and congenital dyserythropoietic anemias.

A patient suffering from chronic hepatitis exhibited severe transfusion reactions after administration of fresh frozen plasma and a plasma fraction: PPSB (prothrombin complex concentrate). 1 month before these reactions, she received fresh frozen plasma during plasma exchange therapy. The patient's serum obtained 1 week and 6 months after the second reaction gave a precipitation arc against PPSB preparations when examined by double-diffusion technique in agarose gel. An antibody of IgG class present in these sera reacted with a purified preparation of the fourth complement component (C4). This was demonstrated by various experiments (protein A radioimmunoassay and passive hemagglutination) using purified C4 as antigen. The antibody had a limited specificity and reacted only with C4 of Rodgers specificity. Phenotype determination of the patient's C4 group showed that she was Chido positive and Rodgers negative. Her HLA group was A1, Aw30; B8,-; DR3,-. The patient had neither detectable anti-IgA nor other anti-immunoglobulin antibodies. She had not received blood or plasma transfusion before her hepatitis. The coexistence of a precipitating anti-C4 antibody and adverse transfusion reactions to plasma fractions containing large amounts of C4 indicates that in the absence of antibodies of other specificities, this antibody can be considered as the cause of the transfusion reaction.

Polyvalent human immunoglobulins for intravenous use (GVP) are obtained by fractionating human plasma with ethanol, according to a method in which traces of pepsin at pH4 eliminate any anticomplementary activity. All the analytical tests have come within official requirements. Results of extended tests concerning specificity, potency, immunoglobulin subclass distribution, biological half-life and opsonic function are presented. Since their official release for clinical use on July 1st, 1983, almost 15,000 therapeutic units of 2.5 g of immunoglobulins have been consumed without any reported major side effects. Multicenter clinical trials are being carried out with adults and children. Available results confirm very good tolerance, and, as expected, effectiveness for well known and codified indications.