Aspects of the lognormal function in the analysis of regional population distribution.

"The spatial structure of population within a metropolitan-area-based region is approached via the population density function, in much the same way as has been undertaken for a city or metropolitan area.... The concern in the balance of the paper is with certain properties lognormal form.... Consideration is given first to properties based on density. The population form of the lognormal function is then derived, and properties based on population are examined. Attention is also given to relationships among density-based and population-based properties." The approach is illustrated using data for London, England, for the period 1971-1981.

Population density functions: a differential equation approach.

"This paper introduces a new mathematical technique to describe population density functions. Two length scales, which characterize the variation of these density functions within a region, are identified. A differential equation is derived and asymptotic solutions obtained. Two specific techniques, the method of matched asymptotic expansions and the method of multiple scales, are introduced and illustrated by application to population densities at both the metropolitan and regional levels."

Association of HLA-Bw65 with two major complotypes.

The association between the HLA-B14 subtypes Bw64 and Bw65 and complement allotypes (C2, Bf and C4) was investigated in both population and family studies. Bf, C4A and C4B allotyping was performed on 37 Bw64 and 35 Bw65 positive unrelated Welsh/English subjects. Sixteen HLA-Bw65 bearing haplotypes were characterized for HLA-ABC, DR and DQ antigens and complement allotypes, including C2. The findings of the population study suggested that the complement haplotype associated with Bw64 is BfS, C4A2, C4B2. The population and family studies revealed two major complement haplotypes associated with HLA-Bw65: (i) C2C, BfF, C4A3, C4A1 - often associated with HLA-A3, Cw8 and DRw13, and (ii) C2C, BfS, C4A2, C4B2 - often associated with HLA-Aw33, Cw8 and DR1 or with A28, Cw8 and DRw13. The HLA-Bw65 bearing haplotypes of three families carried a C4B2B1 duplication of the C4B locus. In these families three C4B gene products were identified in the Bw65 positive members using an anti-C4B monoclonal antibody. It is suggested that most, if not all, HLA-Bw65 bearing haplotypes may possess a C4B locus duplication.

Statement on the nomenclature of dog C4 allotypes.

As a collaborative work of three laboratories the polymorphism of the canine fourth complement component (C4) was studied in a total of 131 unrelated dogs from different breeds and mongrels. Using high voltage electrophoresis followed by an immunoblotting technique, we detected eight distinct variants. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of canine C4 showed an additional heterogeneity of the alpha and gamma chains which resulted in a total of 11 variants in the population studied. So that more precise information concerning the respective C4 allotypes will be available, a nomenclature is proposed designating not only the migration pattern of the C4 variants in agarose gels but also the heterogeneity of the C4 chains observed in SDS-PAGE.

Detection of both isotypes of complement C4, C4A and C4B, in normal human glomeruli.

Monoclonal antibodies reactive against the complement C4A and C4B isotypic components were used in an immunoperoxidase technique for the histological study of normal human renal tissue. Prominent staining with both antibodies was seen in the mesangial areas of all normal kidney sections investigated. Occasional staining of arteriolar walls of the same tissues, however, was also observed. In contrast, no mesangial staining was seen using monoclonal antibodies reactive against other 'early' complement components, such as C1q and C3. Specificity of the glomerular staining with the anti-C4 reagents was demonstrated in two patients possessing only the C4A serum component but lacking genetically the C4B locus products. As would be predicted, glomerular staining with the anti-C4A reagent, but not anti-C4B, was clearly demonstrable. It is concluded that both isotypes of complement C4 are present in normal human glomeruli and thus might be operative for normal mesangial function.

A product of the C4B locus lacking hemolytic activity.

An unusual C4B allotype, C4B 4I, was identified in a study of C4 polymorphism in Japanese. This variant was defined as C4B using a murine monoclonal antibody specific for the C4d region of C4B. Hemolytic assay, however, revealed that the C4 variant, C4 BI was hemolytically inactive in contrast to other well-defined C4B locus products.

Monoclonal antibodies to human beta-interferon produced by adoptive transfer in irradiated mice.

Three murine anti-human beta-interferon (IFN-beta) monoclonal antibodies have been isolated following adoptive transfer of immune spleen cells. Adoptive transfer was used to increase the specific efficiency of the fusion. These antibodies have been used to define two epitopes on IFN-beta; the antiviral, antiproliferative, and immunomodulatory effects of IFN-beta are associated with one of these epitopes.

Immunogenicity of and immune response to the human platelet antigen Zwa is strongly associated with HLA-B8 and DR3.

In a prospective study the immunogenicity of the Zwa antigen during gestation was investigated. Twenty-six out of 1,211 pregnant women were Zwa negative (2.15%). In 2 out of 23 Zwa negative mothers who delivered Zwa positive children, an antibody to Zwa was detected. To determine the relationship between the immune response of pregnant women towards Zwa and the MHC, the phenotype frequencies of HLA-A, B, C, DR, and complement BF, C2, C4A, C4B allotypes of "non-responders" without detectable Zwa antibodies (N = 20) were compared with a group of "responders", i.e. Zwa negative mothers giving birth to Zwa positive children with typical neonatal alloimmune thrombocytopenia (NAIT; N = 39) and with a normal control population. When compared to the normal control group, "non-responders" showed a significant increase of the DRw6 frequency, whereas in the "responders" group HLA-A1, B8, DR3, and C4A*QO were significantly elevated. If "non-responders" and "responders" were directly compared, only B8 and DR3 remained significantly different. The strongest association with a hypothetical immune response gene appeared to exist with DR3.

C4 phenotypic variation suggests an unusual class III gene organization.

The class III gene markers, C4A, C4B, C2 and BF were determined in 26 HLA genotyped families. In 6 of these families the inheritance of the C4A electrophoretic phenotype, C4A 3, A 2 could not be explained assuming the genetic model that the C4A component is controlled by only one locus (C4A) and suggests that both C4A 3 and C4A 2 are encoded by the same chromosome. This apparently duplicated C4A locus haplotype is common in Northern Europeans occurring at a frequency of at least 6%. In 4 families the C4A 3, A 2 'variant' occurred together with HLA-Bw35 and in 2 together with HLA-Bw55. Furthermore, it was striking that in each family the C4A 3, A 2 'variant' was found exclusively with the complotype FC3/20 which encodes no phenotypically expressed C4B locus product.

Possible association between HLA-DR5 and superficial spreading melanoma (SSM).

Previous analyses of possible associations between MHC determinants and cutaneous malignant melanoma (MM) have been inconclusive. We have investigated 98 patients with special emphasis on histologically determined subtypes of MM, and 5 multiple-case families. In addition to HLA-ABC and DR typing, complement allotypes of C2, C4A, C4B, BF were determined. Among the unrelated patients HLA-DR5 and, secondarily, B49 were observed to be associated with superficial spreading (SSM) but not with nodular (NM) or lentigo maligna melanoma (LMM). In families with MM, no definite segregation of the disease according to HLA and complement haplotypes was discernible. Moreover, no coincidence of haplotypes occurred in patients of the different families. HLA region recombinations including B/DR and/or DR/GLO were found in all the families investigated.

Rare variant of complement C4 is seen in high frequency in patients with primary glomerulonephritis.

59 unselected patients with primary glomerulonephritis were phenotyped for alleles of the MHC-linked complement genes, C4A, C4B, and BF. A rare variant of the C4B locus, C4B*2.9, was found in 25% of these patients compared with only 2% of the normal population--a relative risk of 22.1 for glomerulonephritis in individuals with this variant. Subdivision of patients by histological classification of glomerulonephritis revealed a significant association of C4B*2.9 with the membranoproliferative form. There were no significant associations between primary glomerulonephritis or its subtypes and the other HLA markers tested.

HLA-linked complement markers in Alzheimer's and Parkinson's disease: C4 variant (C4B2) a possible marker for senile dementia of the Alzheimer type.

We determined the gene frequencies for the alleles of the HLA-linked complement markers C2, properdin factor B (BF), C4A (Rodgers) and C4B (Chido), and the red cell enzyme glyoxalase-I in 38 unrelated patients with senile dementia of the Alzheimer type, 42 patients with idiopathic Parkinson's disease, and 59 unaffected, aged-matched control blood donors. In senile dementia of the Alzheimer type and in Parkinson's disease, no significant difference was found in the gene frequencies of alleles at either the BF, C2, or GLO-I locus compared with those of age-matched controls. In senile dementia of the Alzheimer type, a striking increase in the frequency of the rare C4B locus allele, C4*B2, was apparent, resulting in the high relative risk of RR = 8.8 (p less than 0.0001) for this disorder.

C4 polymorphism: use of a monoclonal antibody to distinguish C4A and C4B locus products.

A monoclonal antibody reactive against C4B locus products was used in a passive immunoblotting technique to distinguish C4B from C4A electrophoretic variants. The technique is simple and has the advantage of being able to distinguish clearly those C4B variants which may be either difficult to define by conventional hemolytic assay alone or which would normally be designated as C4B products on account of their lack of hemolytic function. Patterns detected by immunoblotting can be compared directly with patterns obtained by immunofixation with anti-C4 from the same gel.

C4 allotyping distinguishes HLA-B14.1 and B14.2 subgroups.

Complement allotyping (C4, C2, and BF) was performed in 60 unrelated individuals and 15 families characterized for the subtypes (14.1 and 14.2) within HLA-B14. Eighty-seven percent of B14.2 individuals typed positive for the rare C4A2 variant. In contrast, less than 7% of B14.1 individuals were positive for this C4 allotype which is in keeping with a control background frequency. Family studies revealed that three distinct complotypes (complement haplotypes) are characteristic for the two HLA-B14 subgroups. The SC22 and FC31 complotypes characterize the B14.2 subtype, whereas SC31 appears to define B14.1.

C4 polymorphism in the dog: molecular heterogeneity of the C4 alpha and C4 gamma subunit chains.

Using an immunoblotting technique and goat antihuman C4, we observed five distinct electrophoretic variants of C4 in a panel of 60 random dogs. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of immunoprecipitated C4 showed that dog C4 is composed of three polypeptide subunit chains (alpha, beta, and gamma) and that structural variability occurs within the alpha- and gamma-chain regions. Two distinct molecular weight forms of both the C4 alpha- (alpha A and alpha B) and C4 gamma- (gamma A and gamma B) chain were detected. The variant forms of C4 alpha and C4 gamma were found in association with particular C4 allotypes.

MHC-linked class III genes. Analysis of C4 gene frequencies, complotypes and associations with distinct HLA haplotypes in German Caucasians.

The class III complement components, C4, C2 and factor B (BF), are encoded in the human major histocompatibility complex (MHC). The two genes determining C4 (C4A and C4B) display considerable polymorphism and, thus, are important markers for HLA. In combination with alleles of C2 and BF they can be grouped into unique complotypes. We have analyzed the C4 alleles in a panel of 204 unrelated German Caucasians and studied their segregation with HLA haplotypes in 24 normal families. Inclusion of the class III markers with the class I and II alleles provides a more refined picture of the genetic structure of the MHC in these families. When charted according to the HLA-B locus specificities the MHCs can be clustered into groups showing distinctly homogenous or heterogenous complotypes. The identification of such groups is valuable for the selection of genetic material to analyze the molecular genetics of the human MHC.

HLA and complement allotypes in Type 1 (insulin-dependent) diabetes.

A group of patients with Type 1 (insulin-dependent) diabetes mellitus was investigated for HLA-A, B and DR antigens as well as C4 and factor B polymorphism. A significant excess of DR3/DR4 heterozygotes was observed (27% versus 17% by Hardy-Weinberg expectation). The factor B allele BfF1 was present in 13% of patients with Type 1 diabetes (gene frequency of 0.08 versus 0.01 in control subjects). A rare C4 B allele, C4 B2.9, was found in 18% of patients with Type 1 diabetes (n = 63) compared with 1.1% of control subjects (n = 176). Total C4 deficiency at the C4 A locus (C4 AQ0,0) was present in 10% of patients with Type 1 diabetes compared with 0% of control subjects. Examination of HLA, C4 and Bf phenotypes in patients with Type 1 diabetes suggested that three high risk supratypes, HLA-A1 B8 BfS C4 AQ0 C4 B1 DR3; HLA-B18 BfF1 C4 A3 C4 BQ0 DR3; HLA-A2 CW3 BW62 BfS C4 A3 C4 B2.9 DR4 are markers for susceptibility alleles.

Analysis of active and inactive complement C4 complotypes associated with subtypes of HLA-B17 in different racial groups.

HLA-A, B, and C antigens and the HLA-linked markers BF, C2, and C4 were determined in 1,799 unrelated Caucasians, 140 North American blacks, 140 Chinese, and 66 Japanese. One allele of the C4A locus (Rodgers), C4A*6, was found to code for a functionally inactive product in HLA-B17 (Bw57)-positive individuals, but for a functionally active product in HLA-B37- or HLA-B27-positive individuals. Further studies revealed that the functionally inactive C4A*6 gene product was found only in one subtype of HLA-B17, namely, 17.1 (Bw57, long). In addition, it was found that the frequency of the other subtype of HLA-B17, namely, 17.2(Bw58, short) varies greatly in different populations and that HLA-Bw58 is associated with either C4A*3,B*1 or C4A*3,B*Q0.