Humoral responses to Pneumocystis carinii in patients with acquired immunodeficiency syndrome and in immunocompromised homosexual men.
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Acquired Immunodeficiency Syndrome↗
Biomedical subjects
P Platz
Publications and source records attributed to P Platz.
Immunological studies in acquired immunodeficiency syndrome. Functional studies of lymphocyte subpopulations.
The lymphocyte transformation response in vitro to mitogens (phytohaemagglutinin, concanavalin A, and pokeweed mitogen) and antigens (purified protein derivative and tetanus) was studied in three patients with acquired immunodeficiency syndrome (AIDS), three patients with pre-AIDS, and six healthy controls before and after depletion of T4- or T8-positive cells. In controls, T8-depleted lymphocytes responded as well as peripheral blood mononuclear cells (PBMC) when monocytes were added, whereas T4-depleted cells gave about 50% of this response to mitogens and no response at all to antigens. No evidence of suppression was seen when various mixtures of T4- and T8-depleted cells were made. In particular, there was a virtually linear relationship between the percentage of T8-depleted cells and the response to antigens. The PBMC of all AIDS and pre-AIDS patients had very low or absent responses to mitogens and antigens, and except in one case, this response did not increase after depletion of T8-positive cells (and addition of monocytes), indicating that these patient cells also lack suppressor activity in this assay. However, a significantly increased response to mitogens was seen when the T8-depleted suspensions were adjusted to contain 20,000 T4-positive cells per well, but the response was still significantly lower than that of similar suspensions from controls. Thus, not only are the poor responses of PBMC from AIDS and pre-AIDS patients due to a low concentration of T4-positive cells, but the responsiveness of these cells also seems deficient. Furthermore, T8-positive patient cells also have an impaired responsiveness. Our experiments do not exclude the possibility that the low response is due to a T8-negative suppressor cell, but it seems more likely that both the T4- and the T8-positive cells are deficient and/or that there is a deficiency in accessory cells. These possibilities are currently under study.
Acquired Immunodeficiency Syndrome↗
The immunodeficiency of bone marrow-transplanted patients. The effect of patient lymphocytes on the response of donor lymphocytes to mitogens and allogeneic cells.
Lymphocytes from patients after bone marrow transplantation (BMT) are in most cases predominantly of the Leu-2+ (cytotoxic/suppressor) phenotypes and are almost unresponsive to mitogens. In contrast, normal Leu-3+-depleted, Leu-2+-enriched lymphocyte suspensions retain approximately 50% of the mitogenic response compared with that of unseparated cells. To investigate whether this discrepancy was due to active suppression, we selected nine BMT patients from whom sufficient numbers of cells were available and whose lymphocyte phenotypes were predominantly Leu-2+ after BMT. These post-BMT lymphocytes were tested for functional suppressor activities against donor and recipient pre-BMT lymphocytes in the lymphocyte transformation test. None of these post-BMT cells suppressed the response of donor or pre-BMT cells to phytohaemagglutinin A or concanavalin A. In contrast, the response of donor cells in mixed lymphocyte cultures to HLA-DR-different third-party cells was suppressed by highly X-irradiated post-BMT cells by approximately 40%. Addition of T-cell growth factor (= interleukin 2 (IL-2)) or X-irradiated donor cells to post-BMT lymphocytes partially restored the mitogenic response. These findings indicate that the early post-BMT cells lack production of IL-2 but are capable of responding to IL-2 and that the almost extinct mitogen response of these cells is due to immaturity rather than active suppression. The suppression of the allogeneic but not the mitogenic response might be explained by differences in the modes of activation; for example, the allogeneic response must involve the T-cell receptor, while the mitogenic response may not.
Bone Marrow Transplantation↗
The impact of low donor-specific MLR versus HLA-DR compatibility on kidney graft survival.
We have analyzed the predictive value on cadaver kidney graft survival of a low stabilized relative response (SRR) in donor-specific mixed lymphocyte culture (MLC). Thirty-eight recipients and donors of cadaver kidneys constituted the case material. The 12-month survival of cadaveric grafts was 83% when the SRR values of the mixed lymphocyte reaction (MLR) between recipient and donor were below or equal to 50 and 40% when the SRR values were above 50. The difference was statistically significant (P less than 0.006). A higher (though not significantly so) graft survival rate was obtained in transplant groups when the recipients and donors were well matched for DR antigens. The 12-month survival was 70% when no DR incompatibilities could be demonstrated and 50% when one or more DR antigens were incompatible. The primary role of MLR matching for the outcome of kidney graft survival is supported by the observation that the influence of the MLR is still significant when stratified for DR matching (P less than 0.05). In conclusion, when adequately stabilized, the specific MLC reactivity of the recipient against the donor is a very important predictive factor for the outcome of cadaver kidney transplantation, which stresses the importance of improvements in serological DR typing.
Cytotoxicity Tests, Immunologic↗
The acquired immunodeficiency syndrome (AIDS) in Denmark. A report from the Copenhagen study group of AIDS on the first 20 Danish patients.
Twenty Danish patients with the acquired immunodeficiency syndrome (AIDS) had been diagnosed by January 1984, 14 of them after 1982. Eighteen patients were male homosexuals, 8 of whom had visited the USA after 1979, 2 were heterosexual males with a history of sexual contacts in Central Africa, suggesting a transmission of AIDS from woman to man. AIDS has not been observed in drug abusers, hemophiliacs or transfused non-risk persons in Denmark. The clinical picture varied according to the presence of Kaposi sarcoma or the type of opportunistic infections, but was in general similar to that reported from the USA. Investigation of T-lymphocyte subsets revealed that the AIDS patients differed from controls and healthy homosexual men by having either a very low number of helper cells or a low helper/suppressor cell ratio. Functional immunological studies revealed a decreased natural killer cell activity and decreased blast transformation by mitogens. The survival two years after diagnosis was 16%.
Acquired Immunodeficiency Syndrome↗
An unusual case of multiple malignancy in an adult.
An adult female is described who, during a clinical course of 25 years, presented malignant tumors of the rectum, breast, uterus and colon. Cytostatics were never administered. Lymphocyte subsets, a variety of lymphocyte and mononuclear cell stimulation assays with mitogens and antigens, DNA repair tests and activity of natural killer cells were normal. Serum leukocytic interleukin-1 activity was slightly elevated. Sister chromatid exchange frequency in peripheral lymphocytes was below the normal range. An explanation for the development of 4 primary malignant neoplasms was not found.
Breast Neoplasms↗
Linkage between late onset, dominant spinocerebellar ataxia and HLA.
Three families with at least three generations of family members affected with spino-cerebellar ataxia transmitted in a dominant fashion were studied. In each family every available member, above the lowest age at onset observed in that family, was subject to a thorough clinical investigation and blood was sampled for HLA,A, B and C-typing. In all three families the affected members had signs which were characteristic for cerebellar ataxia, without spasticity or dementia. In two families the mean age at onset was in accordance with the literature, viz. in the fourth and fifth decade, while in the third family mean age at onset was over 50 years. In the two pedigrees with the usual age at onset there was evidence of linkage between the disease and the HLA-system with a combined lod score of 1.499 at a recombination fraction of 0.05 for males. The third pedigree gave negative lod scores for linkage between HLA and the disease locus for both males and females but in this family also the high age at onset was indicative of genetic heterogeneity.
Adult↗
The impact of HLA-DR compatibility on cadaver kidney graft survival in a prospective study with special emphasis on the quality of typing.
The survival data of 151 consecutive cadaver kidneys transplanted by the two transplantation centres of Copenhagen from September 1, 1980 to September 30, 1982 with an observation period of at least 3 months have been analyzed. The HLA-DR types could not be established in 4 out of 130 donors. In most of the analyses only the well-defined antigens DR1, 2, 3, 4, 5, 7, and w8 were included. Inclusions of the DRw6, w9, and w10 antigens in the matching did not change the results. The one-year graft survival (GS) was 72.1% for 97 HLA-DR compatible kidneys as compared to 41.4% for 49 incompatible kidneys (p = .0007); this difference remained highly significant when stratified for the recipient status of pretransfusion, risk, and age. Non-transfused recipients had a fairly good GS but had received significantly better matched kidneys than the remaining recipients. The transfusion "effect" became barely significant (p = .054) when stratified for DR. There was no significant influence of donor or recipient DRw6-type as defined in this study. The GS was not significantly influenced by HLA-A, B matching, recipient antibody status, B cell cross-matches, transplant, or donor centre. Special efforts were made to assign the HLA-DR phenotypes of the recipients and donors as accurately as possible. In 39 cases, there was a discrepancy between the result of the acute DR-typing of the donor and the final result based on subsequent typings. The acute DR match had no influence on GS in these recipients whereas the final match had a significant influence in the same group, which in a way comprise a randomized trial. In the total material, the acute DR match still showed an influence on GS, but the significance decreased by a factor 20. This illustrates how the quality of DR typing may influence the results of the analyses. The overall GS (62.5%) was significantly (p = .05) better in this series than that (48.2%) in our preceding series, but it is uncertain whether this is due to better matching alone.
Cadaver↗
HLA-D region beta-chain DNA endonuclease fragments differ between HLA-DR identical healthy and insulin-dependent diabetic individuals.
The human HLA-D histocompatibility region encodes class II antigens each of which consists of two polypeptide chains (alpha and beta) inserted in the plasma membrane. These molecules are implicated in the regulation of the immune response but several human diseases are also found to be associated with certain HLA-DR antigens. The occurrence of insulin-dependent (type I) diabetes (IDDM) is strongly associated with HLA-DR3 and/or 4 (ref. 5). The class II antigens, however, show a marked genetic polymorphism associated with the beta-chains which seem, from hybridization studies, to be encoded by several genes. We have therefore used the beta-chain cDNA probe, pDR-beta-1 (refs 8, 10) to test whether there are differences in hybridization pattern between DNA from healthy individuals and diabetic patients, after digestion with restriction endonucleases. Among the HLA-DR 4 and 3/4 individuals, the IDDM patients showed an increased frequency of a PstI 18 kilobase (kb) fragment. A BamHI 3.7 kb fragment, frequent among controls (30-40%), was rarely detected in the IDDM patients (0-2%). These differences may be related to susceptibility to develop the disease.
DNA Restriction Enzymes↗
Detection of HLA-D/DR-related DNA polymorphism in HLA-D homozygous typing cells.
Sequences of different sizes are generated when DNA from homozygous HLA-Dw/DR typing cells are digested with restriction endonuclease and analyzed by hybridization with a HLA-D region class II antigen beta-chain cDNA probe. The patterns of hybridization were highly polymorphic but one endonuclease, BamHI, defined sequences unique to all HLA-Dw/DR specificities 1-8 except HLA-Dw/DR 2 and 6; however, these two specificities were resolved with the enzyme EcoRI. Digestion with other endonucleases such as Pst I results in patterns of restriction fragments that differ between homozygous typing cells of the same HLA-Dw/DR specificity. HLA-D region beta-chain probes permit HLA-D region genotyping at the DNA level and may allow detection of genes controlling the association of HLA specificities with a wide variety of diseases.
DNA↗
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↗
HLA and disease 1982--a survey.
Within the last 7 years, HLA and disease studies have made it clear that most of the diseases previously known to be HLA-A- or B-associated do in fact show stronger associations with HLA-D/DR antigens. This observation strengthens the assumption that Ir and/or Is determinants are responsible for these associations in agreement with the fact that many of these diseases are characterized by autoimmune phenomena. However, some diseases, ankylosing spondylitis in particular, still show stronger associations with HLA-ABC than with DR antigens. Among the conditions which have been shown to be HLA-associated more recently, four deserves special mention: (i) maternal immunization against the Zwa antigen because this is a good candidate for an antigen-specific Ir gene action; (ii) IgA deficiency in blood donors because this is a non-antigen-specific immunodeficiency; (iii) idiopathic hemochromatosis and (iv) congenital adrenal hyperplasia due to 21-OH deficiency because immune mechanisms are unlikely to be involved. HLA studies and new genetic methodology have significantly advanced our knowledge about the inheritance of some diseases. Thus, HLA-B27 or a B27-associated HLA factor confers a dominant susceptibility to ankylosing spondylitis. HLA plays a definite and strong role in the susceptibility to IDDM, but simple genetic models (dominant, recessive, and intermediate) have been made unlikely on the basis of HLA results; the hypothesis that there are two different susceptibility genes within the HLA system still remains viable, but the demonstration of clinical heterogeneity and/or (better) of different pathogenetic pathways for DR3- and DR4-associated IDDM is required to substantiate it.
Cerebellar Ataxia↗
Heterozygous expression of insulin-dependent diabetes mellitus (IDDM) determinants in the HLA system.
HLA phenotypes of cases with insulin-dependent diabetes mellitus (IDDM) and identity by descent of HLA haplotypes in affected sib-pairs support an intermediate model in which morbid risk is increased by one HLA-linked IDDM determinant, and greatly increased by two determinants, which may be qualitatively different in DR3 and DR4 haplotypes. Linkage analysis allowing for gametic disequilibrium reveals no recombination in pedigrees with a DR3/DR4 propositus, but spurious recombination in the remaining pedigrees. This evidence favors interaction of unlinked IDDM determinants to produce affection in a small proportion of heterozygotes for an HLA-linked determinant. Partition of data by HLA type of the propositus (ideally by DR and the complement types jointly) is a powerful method to resolve etiological heterogeneity for HLA-associated diseases.
Adult↗
No evidence for linkage between HLA and maturity onset type of diabetes in young people.
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ABO Blood-Group System↗
Typing for human alloantigens with the primed lymphocyte typing technique.
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Animals↗
Frequency of nine HLA-D antigens in the Danish population.
The frequency of HLA-Dw1-8 and DH was determined in 389 unrelated healthy Danes and in 257 kidney patients. All individuals were HLA-A, B, C typed, 168 of the normal individuals and all kidney patients were typed for HLA-DR. The frequency of Dw1-8 in the normal material and kidney patient material was quite similar except for Dw6, which showed an increased frequency among the kidney patients, but as the patients are not prospectively ascertained, the significance of this finding is unclear. The frequency of the blank allele is 0.19 which is comparable to other Scandinavian materials but much lower than that seen in the joint report of the 8th International Histocompatibility Workshop. The D frequencies correlate quite well with the HLA-DR frequencies, the biggest discrepancy between D and DR exists for D/DR4, where DR4 is much "broader". The DR4 positives can be divided into the Dw4 positives, strongly associated with B15 and the Dw4 negatives, not associated with B15 but with B40. Primed lymphocyte typing in some cases followed HLA-DR, in other cases HLA-D assignment. For HLA-D/DR2 the DR assignment also seemed to be broader, the DR2 positive, Dw2 negative group not being associated with B7, but possibly with B5. In the assignment of HLA-D determinants, "false negatives" have caused problems in many materials, but the inclusion of a number of known control responders in our experiments has made it possible to increase the accuracy of assignment by adjusting the cut-off level for typing responses according to the typings of the controls.
Denmark↗
Genetic studies of insulin-dependent diabetes mellitus: segregation and linkage analyses.
The inclusion of HLA data in genetic studies of insulin-dependent diabetes mellitus (IDDM) has not led to conclusive segregation models for IDDM so far. As a new approach, we first applied complex segregation analysis, independently of HLA data, to two combined Danish family materials. Then the best fitting segregation model was entered into linkage analysis of a third material, including family as well as HLA data. The best solution obtained in the segregation analysis was a mixed model, including an intermediate gene, which on the penetrance scale acts as a recessive, together with a polygenic component. The linkage analysis showed an overall recombination fraction of 0.0417 with high coupling frequencies for the HLA-DR3 and HLA-DR4 alleles and the putative disease susceptibility gene. However, when the pedigrees were divided according to whether or not the proband had the heterozygous HLA-phenotype DR3/DR4, a maximum likelihood ratio test for heterogeneity was significant, with estimated recombination fractions of 0.0 and 0.0963 in HLA-DR3/DR4 pedigrees and the remaining pedigrees, respectively. In total, we found convincing evidence that two familial factors contribute to IDDM: a locus within HLA, which very well may be DR; and an unlinked mechanism which is unimportant for HLA-DR3/DR4 but simulates recombination. If confirmed, this conclusion has important implications for further genetic studies of IDDM and complex segregation analyses of family materials sampled according to criteria which include HLA data of the probands are highly needed.
Adolescent↗
HLA and heterogeneity of multiple sclerosis.
Age at onset, debut symptoms, optic nerve signs, and severity of symptoms were evaluated from the medical records of 135 patients with MS. HLA-D/DR2 was significantly more frequent in rapidly progressive MS, and D/DR2 seemed to confer both susceptibility to the disease and to more rapid progression. However, D/DR3 seemed to protect against rapid progression.
Adult↗