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Biomedical subjects

C A Alper

Publications and source records attributed to C A Alper.

At least 73 records · Page 4Linked to original sources
PubMed1991

The cellular basis for lack of antibody response to hepatitis B vaccine in humans.

We had previously obtained evidence that among normal subjects the humoral antibody response to hepatitis B surface antigen (HBsAg) was bimodally distributed with about 14% of subjects producing less than 1,000 estimated radioimmunoassay RIA units. From the study of major histocompatibility complex (MHC) markers in the very poor responders who produced less than 36 estimated RIA units of antibody, it appeared that there was an excess of homozygotes for two extended haplotypes [HLA-B8, SC01, DR3] and [HLA-B44, FC31, DR7]. This finding suggested that a poor response was inherited as a recessive trait requiring nonresponse genes for HBsAg on both MHC haplotypes and was strengthened by finding a much lower antibody response among prospectively immunized homozygotes for [HLA-B8, SC01, DR3] compared with heterozygotes. In the present study, we have analyzed the cellular basis for nonresponse to this antigen by examining antigen-specific proliferation of T cells from responders and nonresponders in the presence and absence of autologous CD8+ (suppressor) cells. Peripheral blood cells from nonresponders to HBsAg failed to undergo a proliferative response to recombinant HBsAg in vitro, whereas cells from responders proliferated vigorously. This failure of cells from nonresponders to proliferate was not reversed in cell mixtures containing CD4+ and antigen-presenting cells devoid of CD8+ cells. There was no difference between responders and nonresponders with respect to the number of circulating T cells or their subsets, or the proliferative response to mitogens such as pokeweed or phytohemagglutinin or another antigen, tetanus toxoid. Our results indicate that our HBsAg nonresponding subjects have a very specific failure in antigen presentation or the stimulation of T helper cells, or both. Our evidence is against specific immune suppression as the basis for their nonresponsiveness. The failure of antigen presentation or T cell help is consistent with recessive inheritance of nonresponsiveness and suggests that response is dominantly inherited.

Antibody Formation↗
PubMed1991

Association of polymorphisms in the HLA-B region with extended haplotypes.

Genomic probes from the HLA-B region of the major histocompatibility complex (MHC) were used to study the association of restriction fragment length polymorphisms (RFLPs) with various MHC alleles, complotypes, and extended haplotypes. The two DNA probes, M20A and R5A, were derived from previously cloned cosmids and are located 38 and 110 kilobases (kb) centromeric to HLA-B, respectively. Five different RFLP variants occurring in five different haplotypic combinations were detected within a panel of 40 homozygous-typing cells and cells from 21 families using Bst EII. In two informative families with HLA-B/DR recombinations the inheritance of the RFLP variants was consistent with their mapping between HLA-B and complotypes. The R5A/M20A haplotypic pattern 6.5 kb/3.0 kb (A) had a normal Caucasian frequency of approximately 0.43 and was found in all independent examples of the extended haplotypes [HLA-B8,SC01,DR3], [HLA-B18,F1C30,DR3], [HLA-Bw62,SC33,DR4], [HLA-B44,SC30,DR4], and [HLA-Bw47,FC91,0,DR7]. The patterns 6.9 kb/3.0 kb (B), 6.5 kb/4.7 kb (C), 1.45 kb/3.0 kb (D), and 6.9 kb/4.7 kb (E) had normal Caucasian frequencies of approximately 0.23, 0.15, 0.15, and 0.04 and were found on all independent examples of [HLA-B38,SC21,DR4], [HLA-Bw57,SC61,DR7], [HLA-B7,SC31,DR2], and [HLA-B44,FC31,DR7], respectively. Individual complotypes or HLA-B alleles which were markers of extended haplotypes showed variable associations. For example, HLA-B7 and the complotype SC31 were associated with all R5A/M20A RFLP haplotypes except haplotype E, although [HLA-B7,SC31,DR7] was associated exclusively with haplotype D. HLA-B27, not known to be part of an extended haplotype, was surprisingly exclusively associated with the 6.5 kb/4.7 kb or C haplotypic pattern in all five instances tested. These findings support the concept of regional conservation of DNA on independent examples of extended haplotypes. The results also further characterize these haplotypes.

Alleles↗
PubMed1991

Decreased inhibition of immune precipitation by sera with the C2 B allotype.

Complement-mediated precipitation inhibiting (CMPI) activity of sera of 5 individuals homozygous for C2 B was compared to that of sera of 20 individuals carrying the common C2 C allotype. Sera with the rare C2 B allotype had a depressed CMPI capacity in both the early (5 min) and the late (60 min) stages of the reaction. We have also compared the CMPI activity of seven homozygous C4A deficient (C4A*Q0) and eight C4B deficient (C4B*Q0) serum samples and did not find significant differences from the controls (no C4 null alleles) in any stage of the reaction. These results indicate that C2 is the critical component in the CMPI reaction of the two constituents of the classical pathway C3 convertase and that C2 B is less active than C2 C.

Antigen-Antibody Reactions↗
PubMed1991

A restriction fragment of the C2 gene is a unique marker for C2 deficiency and the uncommon C2 allele C2*B (a marker for type 1 diabetes).

There are three common C2 protein alleles in caucasians, C2*C, C2*B, and C2*Q0, with allele frequencies of 0.96, 0.03, and 0.01, as well as Sst I RFLP variants of 2.75, 2.7, 2.65, 2.55, and 2.4 kb, with frequencies of 0.017, 0.533, 0.358, 0.017, and 0.075. Thus, C2*C is informatively split by the RFLP. Of 94 nonrandomly ascertained caucasian complotypes, 77 contained C2*C, four contained C2*Q0, and 13 had C2*B. None of the C2*C-containing complotypes carried the 2.75 kb Sst I fragment and all of the complotypes with C2*B or C2*Q0 carried it. All of the C2*Q0 alleles were associated with C4A*4, C4B*2 in the complotype S042 as previously reported. C2*B was usually (9/13) in the complotype SB42, occasionally (1/13 each) in SB45, SB41, SB(4,3)0, and SB31. Thus, the association of the C2 2.75-kb fragment was with C2*B and C2*Q0, not with C4A*4, C4B*2, or even C4A*4 alone. The complotype SC42 was associated with the 2.65-kb Sst I fragment in four of five instances and in a single example with the 2.7-kb fragment. C2*B and C2*Q0 possibly had a common evolutionary ancestor complotype which carried the 2.75-kb Sst I fragment, and BF*S, C4A*4, and C4B*2. C2*B (particularly as the haplotype HLA-Bw62, SB42, DR4) is associated with type 1 diabetes but C2*Q0 is protective.

Alleles↗
PubMed1991

Specific association of HLA-DR4 with increased prevalence and level of insulin autoantibodies in first-degree relatives of patients with type I diabetes.

First-degree relatives of patients with insulin-dependent (type I) diabetes (n = 264 from 106 families) were evaluated with HLA typing and determination of competitive insulin autoantibodies (CIAAs) and islet cell autoantibodies (ICAs). The levels of CIAAs in 30 relatives exceeded our upper limit of normal (greater than or equal to 39 nU/ml), and 30 had high-titer ICAs (greater than or equal to 40 Juvenile Diabetes Foundation units [JDF U]). Eleven of the HLA-typed relatives developed diabetes during follow-up. Twenty-three percent (28 of 123) of the relatives with at least one HLA-DR4 allele were CIAA+ (CIAA greater than or equal to 39 nU/ml) versus 4% (6 of 141) among DR4- relatives (P less than 0.0001). Twenty-one of 22 of the highest CIAA values were all in the DR4+ group (DR4+ vs. DR4-, P = 0.003, Wilcoxon's rank-sum test). HLA-DR3 did not correlate with the level of CIAAs, and neither DR3 nor DR4 correlated with titer of ICAs measured in JDF U. We conclude that, in first-degree relatives of patients with type I diabetes, there is a striking association with HLA-DR4 in both the prevalence of relatives exceeding the normal CIAA range and in the level of CIAAs. These data suggest that a gene on HLA-DR4 haplotypes contributes to the level of anti-insulin autoimmunity, and we hypothesize that DR4-associated diabetes susceptibility, distinct from DR3-associated susceptibility, may be secondary to this influence.

Autoantibodies↗
PubMed1990

The effect of ethnicity on major histocompatibility complex complement allotypes and extended haplotypes in patients with systemic lupus erythematosus.

Previous studies of patients with systemic lupus erythematosus (SLE) have shown an increased frequency of certain major histocompatibility complex (MHC) markers, including HLA-DR2, DR3, and C4AQ0 (C4A-null), in Caucasian patients. However, most of these studies were of randomly selected, unrelated patients; families were not included, and haplotypes were not determined. In order to define more accurately the possible role of MHC genes in lupus susceptibility, HLA-A, B, C, and DR, as well as BF, C2, C4A, C4B, and GLO, markers were determined in 62 Caucasian patients of known ethnic background, and in the members of their families. The distributions of extended haplotypes (fixed combinations of HLA-B, DR, and complotype alleles), fragments thereof, and individual alleles were determined in SLE patients and controls. The MHC distributions in all patients were compared with haplotypes in a normal Caucasian population. There were no statistically significant differences between the frequencies of any MHC marker, fragment, or extended haplotype in the patients compared with the controls. The patients were categorized into 2 groups of European ancestry (English/Irish; other Europeans), and each group was compared with a group of ethnically matched controls. There was a statistically significantly increased frequency of the alleles C4AQ0 and DR3 and the complotype SC01 in SLE patients of English/Irish descent as compared with ethnically matched controls. The increase in C4AQ0 and DR3 could be accounted for by the fact that they were part of the extended haplotype [HLA-B8;SC01;DR3] and/or its fragment (SC01;DR3). No increase in any MHC marker was observed in the other patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Complement System Proteins↗
PubMed1990

Major histocompatibility complex genes and susceptibility to systemic lupus erythematosus.

Susceptibility to systemic lupus erythematosus is associated with major histocompatibility complex (MHC)--encoded genes. We have used nucleotide sequence analysis to better define the disease-associated MHC alleles. HLA-DR2, DQw1, and especially the rare allele DQ beta 1. AZH confer high relative risk (RR = 14) for lupus nephritis in a Caucasian population of patients. Pilot studies using historical controls suggest that these genes also confer a high risk in non-Caucasian ethnic groups (RR = 24-78). We have found that DR4 is significantly decreased in patients with lupus nephritis. Fifty percent of the patients with lupus nephritis had either the DQ beta 1.1, the DQ beta 1.AZH, or the DQ beta 1.9 alleles. These alleles share amino acid residues that have been predicted to be the contact points for antigen and the T cell receptor. These HLA alleles appear to have a direct role in the predisposition to lupus nephritis, whereas DR4 may have a "protective" effect.

Alleles↗
PubMed1990

HLA-DQ RFLP variants of five HLA-DQw2-bearing major histocompatibility complex extended haplotypes.

We have analyzed genomic DNA in a large number of independent examples of five HLA-DQw2-bearing extended haplotypes for their associated subtypes by restriction fragment length polymorphism (RFLP) using DRB, DQA, and DQB probes after Taq I and Pst I digestion and Southern blotting. In addition to three previously described HLA-DQw2 subtypes, DQw2a, DQw2b, and DQw2c, we observed a fourth subtype, HLA-DQw2d, characterized by 5.8 kilobase (kb) DRB/Taq I, 2.4, 2.3, and 1.8 kb DQB/Taq I, and 8.0 and 2.3 kb DQA/Pst I fragments. All 22 independent examples of the extended haplotype [HLA-B8, SC01, DR3] carried DQw2a and all 11 independent examples of [HLA-B18, F1C30, DR3] carried DQw2b. In addition, all independent examples (21 and 4, respectively) of two DR7-carrying extended haplotypes, [HLA-B44, FC31, DR7] and [HLA-Bw47, FC91,0,DR7], carried DQw2c and all independent examples of [HLA-Bw57, SC61, DR7] carried DQw2d. Our results show that the DNA in the DR/DQ region of extended haplotypes is relatively fixed and that different DQw2 subtypes characterize different DQw2-bearing extended haplotypes.

Blotting, Southern↗
PubMed1990

Complotypes in individuals of African origin: frequencies and possible extended MHC haplotypes.

We analyzed the frequency distribution of 106 complotypes [four allele sets of the major histocompatibility complex (MHC) genes for the complement proteins factor B, C2, C4A, and C4B] from 32 Black families residing in Boston and Washington, DC. Twenty-five different complotypes were identified, among which there were four complotypes that had not been previously observed in our large database of complotypes compiled from family studies of Boston Caucasians and that are, presumably, unique to individuals of African origin. These four African-derived complotypes are FC(1,90)0, FC63, S1C2, 17, and SC(3,2,90)0. The frequencies of two of these four unique Black complotypes, FC(1,90)0 and FC63, were increased significantly when compared to Caucasians (pcorr less than 0.00042, pcorr = 0.00294, respectively). The complotype FC(1,90)0 was in positive linkage disequilibrium with HLA-DR3 haplotypes containing the B locus antigens Bw42, Bw52, Bw53, and Bw58, while FC63 was associated with HLA-Bw70, -DR5. These findings demonstrate the extensive polymorphism of complotypes in Blacks, and also suggest that it may be possible to define unique extended haplotypes of African origin.

Alleles↗
PubMed1990

Complotypes in pemphigus vulgaris: differences between Jewish and non-Jewish patients.

Haplotypes of alleles of the major histocompatibility complex (MHC) complement genes BF, C2, C4A, and C4B are inherited as single highly polymorphic genetic units called complotypes. There are about a dozen complotypes with frequencies above about 0.01 in Caucasians. In the blistering disease pemphigus vulgaris, the complotypes SC21 and SB45 were found to be markedly elevated in patients compared with general Caucasian controls. The SC21 increase was in Ashkenazi Jewish patients exclusively (relative risk = 17 in that population), whereas SB45 was found solely in non-Jewish Caucasians (specific population relative risk = 57). Although these are unusually high relative risks, it is most unlikely that these complotypes represent susceptibility genes for pemphigus vulgaris. Rather, it is probable that they mark extended major histocompatibility complex haplotypes with fixed DNA so that independent examples in the population have the same alleles. It is likely that it is the class II genes on these haplotypes that confer susceptibility.

Complement C2↗
PubMed1990

Major histocompatibility complex markers and red cell antibodies to the Rh (D) antigen. Absence of association.

Between 20 and 35 percent of Rh(D) antigen-negative individuals do not develop antibodies to D even after multiple transfusions of Rh-positive red cells. To evaluate the possibility that antibody production after exposure to the D antigen was related to a major histocompatibility complex immune response gene, analysis of the HLA genotypes of 38 Rh-sensitized women and their families was performed. No significant deviations were found in the frequency of any individual HLA class I, II, or III allele or of any extended haplotype (fixed allelic combinations of HLA-B, HLA-DR, and the complement components BF, C2, C4A, and C4B). Type 1 errors due to the extreme allelic polymorphism of the HLA system, as well as the ethnic variation in patient groups, may have contributed to HLA allele-antibody responder relationships reported in earlier studies.

Female↗
PubMed1990

Major histocompatibility complex haplotype studies in Ashkenazi Jewish patients with pemphigus vulgaris.

Of 26 Ashkenazi Jewish patients with pemphigus vulgaris, 24 (92.3%) carried the major histocompatibility complex (MHC) class II alleles HLA-DR4, DQw3, of which all were of the subtype DR4, DQw8. From studies of the patients and their families, haplotypes were defined. It was found that, of the patients who carried HLA-DR4, DQw8, 75% carried one or the other (and in one case, both) of two haplotypes [HLA-B38, SC21, DR4] or HLA-B35, SC31, DR4. The former is a known extended haplotype among normal Jews, with a frequency of 0.102, and the latter may also be an extended haplotype in this ethnic group, with a frequency of 0.017 among normal haplotypes from Jews. Of the remaining DR4-positive patients, all but one had a presumed D-region segment (defined as SC21, DR4, DQw8 or SC31, DR4, DQw8 with variable HLA-B) of these haplotypes. Only one patient had DR4, DQw8 without any other markers of the extended haplotypes. The number of homozygotes and heterozygotes for DR4, DQw8 was consistent with dominant but not recessive (P less than 0.01) inheritance of a class II or a class II-linked susceptibility gene for the disease. Since the disease is entirely attributable to the presence of an antibody to an intraepidermal intercellular cement substance, it is likely that the class II susceptibility gene (on [HLA-B38, SC21, DR4, DQw8], HLA-B35, SC31, DR4, DQw8, or their segments, in Jewish patients) controls the production of the antibody as a dominantly expressed immune response gene.

Alleles↗
PubMed1990

HLA extended haplotypes in childhood and adult onset HLA-DR4-associated arthropathies.

Alpha HLA-DR4 extended haplotypes have been established by family studies in children and adults with chronic arthritis, the children having polyarticular juvenile rheumatoid arthritis and the adults rheumatoid arthritis. These diseases are probably the same disorder presenting at different ages. The results demonstrate age-related differences in the frequency of HLA-DR4 extended haplotypes between the two groups of patients. The childhood onset was associated with the presence of the HLA-B44, SC30, DR4 extended haplotype, whereas the adult form was more strongly associated with the HLA-Bw62, SC33, DR4 haplotype. These results suggest that differences in the age at onset are influenced by the MHC in addition to the presence of the HLA DR4 gene itself.

Adult↗
PubMed1990

C4 nomenclature statement (1990).

A common and revised nomenclature of the allotypes of the fourth component (C4) of human complement has been proposed. It is based on the results of the C4 Reference Typing of the VIth Complement Genetics Workshop and Conference, Mainz, FRG, 1989, the previous C4 nomenclature and the guidelines for human gene nomenclature (ISGN). The designation of allotypes derives from their relative electrophoretic mobility, the distinction between C4A and C4B proteins from their relative hemolytic activity. Common alleles retain their single digit numeric designation, intermediate variants their two- or three-digit designations; newly discovered alleles should not interfere with already described variants. At least 13 C4A alleles, 16 C4B alleles as well as non-expressed genes at each C4 locus are presently known. There are also duplicated loci of each C4 gene; they should be designated by repetition of the locus symbol at the haplotype or genotype level. As a phenotype they will be placed in parenthesis without repetition of the locus symbol. Aberrant allotypes or hybrid genes should be explained by a special suffix. No special nomenclature is recommended for restriction fragment length polymorphisms. Their designation should follow the general rules of the ISGN.

Alleles↗
PubMed1989

Genetic prediction of nonresponse to hepatitis B vaccine.

In previous studies of the antibody response to hepatitis B vaccine in 598 subjects who received a full course of vaccination, we observed a bimodal response, with about 14 percent producing less than approximately 1000 radioimmunoassay (RIA) units. An analysis of the major histocompatibility complex (MHC) HLA and complement types of 20 of the subjects with the lowest responses indicated a greater-than-expected number of homozygotes for the extended or fixed MHC haplotype [HLA-B8, SC01, DR3]. This finding suggested that the lack of a normal response was a recessive MHC-linked trait. In this study, we prospectively vaccinated five homozygotes and nine heterozygotes for this haplotype in the expectation that the homozygotes would produce much lower levels of antibody than the heterozygotes. When the antibody response was assessed two months after the third injection, four of the five homozygotes had produced very low levels (approximately 1000 units or less) of antibody (mean, 467 RIA units; range, less than 8 to 1266), whereas all nine heterozygotes produced more than 2500 RIA units (mean, 15,608; range, 2655 to 28,900) (P less than 0.01). We conclude that the usual response to hepatitis B surface antigen is due to the presence of a dominant immune-response gene in the MHC and that a low response is due to the absence of such a gene and the presence on both chromosomes of MHC haplotypes (such as [HLA-B8, SC01, DR3]) that indicate such a response.

Adolescent↗
PubMed1989

Quantitative variation of C4 variant proteins associated with many MHC haplotypes.

C4 protein variants were analyzed in 64 individuals, of which 51 were either homozygous or heterozygous for an extended major histocompatibility complex (MHC) haplotype (a fixed combination of MHC alleles). The relative amount of each C4 variant was measured by densitometric scanning of stained immunofixed electrophoretic patterns of neuraminidase- and carboxypeptidase-treated samples. The relative concentrations of C4 variants on any haplotype were stable and inherited in families. In five of the eight extended haplotypes investigated, the amount of one of the C4 variants relative to others in the same pattern was increased: [HLA-B8, SC01, DR3] and [HLA-B7, SC31, DR2] produced an approximately doubled amount of C4B1; [HLA-B18, S042, DR2] an increased amount of C4B2; and [HLA-B44, SC30, DR4] a double amount of C4A3. The extended haplotype [HLA-Bw57, SC61, DR7] gave rise to two to three times as much C4B1 as C4A6. In the extended haplotypes [HLA-B44, FC31, DR7] and [HLA-Bw62, SC33, DR4], the results did not clearly indicate differences in expression of the C4 isotypes. DNA analysis possibly supported an actual gene duplication only for the haplotype [HLA-B7, SC31, DR2]. The results suggest that, in addition to variation in the number of structural genes, other MHC-linked mechanisms may be involved in the regulation of the relative amounts of C4A or C4B protein specified by any haplotype.

Complement C4↗
PubMed1989

Complotypes and extended haplotypes in laboratory medicine.

The region on the short arm of the sixth human chromosome encoding class I and class II histocompatibility antigens involved in immune recognition also encodes a group of molecules unrelated to HLA termed class III which includes C2, C4, and factor B. The four genes encoding the complement proteins occupy about 120 kb of genomic DNA between HLA-B and HLA-DR and are closer to HLA-DR. The four genes are inherited as a single unit, without observed crossover, called a complotype, designated by its BF, C2, C4A, and C4B alleles. There are about fifteen complotypes with frequencies of 0.01 or higher on normal caucasian chromosomes. Analysis of linkage disequilibrium between HLA-B, HLA-DR alleles, and complotypes reveals that about 30% of normal caucasian chromosomes consist of fixed sets called extended or fixed haplotypes. There are over a dozen such extended haplotypes defined by their HLA-B, DR and complotype alleles. They appear to contribute most of the previously described linkage disequilibrium between HLA-A/HLA-B and HLA-B/HLA-DR allelic pairs as well as most of the known HLA marker-disease associations. It is postulated that extended haplotypes consist of fixed DNA over at least the 10(6) base pairs of the HLA-B-DR interval, and independent examples in apparently unrelated individuals are thus identical or nearly identical over this interval. A practical consequence of this concept is the possible prediction of successful tissue transplantation donor-recipient pairs.

Chromosome Mapping↗