Hereditary autoimmune thrombocytopenic purpura: an immunologic and genetic study.
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Biomedical subjects
Publications and source records attributed to R Winchester.
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Three groups of cleft palate patients were evaluated for hearing impairment and secretory otitis at age five to determine the effect of myringotomy and tube placement. Each group consisted of 23 patients (46 ears). Hearing levels and otoscopic evaluations were obtained retrospectively from medical records. Group I had had no myringotomies. Group II had myringotomies after the initial palate closure and only when deemed necessary. Group III had had myringotomies at the initial palate closure and subsequently as needed. Optimal timing for myringotomy in cleft palate patients to maximize hearing at school age could not be determined. The need for myringotomy must be determined by clinical judgement on an individual basis.
Seventy patients who underwent craniofacial reconstruction were screened by otological and audiological examinations. Thirty-seven patients had visible ear pathology, thirty-six had conductive hearing impairments. No sensorineural losses were detected. The high incidence of otological pathology in craniofacial patients emphasizes the importance of multi-disciplinary care. Otological rehabilitation should be integrated into the treatment plan to provide maximum function throughout the period of craniofacial reconstruction. Suggestions are made to facilitate communication in the immediate post operative period.
The Ia alloantigens as measures of different alleles of loci in the major histocompatibility complex were determined in patients with systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA). The Ia specificities of reagents used were defined by their pattern of reaction with lymphoblastoid lines derived from normal donors homozygous for HLA-D determinants. The reagent specificities included those associated with a single Dw type as well as those reacting with a single specificity shared by several Dw types. Patients with RA had a marked elevation in the frequency of alloantigens detected by reagent sera that recognize various determinants shared by cell lines from HLA-Dw4, Dw7, or Dw10 individuals (Ia 4-7-10). The frequency of mixed lymphocyte culture alleles Dw4 and Dw10 was found to be increased; however this elevation did not approach the higher frequency for the serologically determined antigens of the Ia 4-7-10 group. In contrast, patients with SLE had an increased frequency of reactions with the reagent alloantisera defined by reactions with either HLA-Dw2 or Dw3 positive cell lines. The data suggest that immunogenetic factors are relevant to both groups of patients, but that these are entirely distinct for each disease.
The "Ia-like" antigens characteristically present on the membrane of B lymphocytes were shown to be absent in most terminally differentiated Ig-producing plasma cells. This was most evident in analyses of myeloma plasma cells that uniformly lacked the Ia-antigens. Also, in B lymphoid cell lines, the lymphoblasts were uniformly Ia-positive but the plasma cells were negative. In contrast, however, the majority of plasma cells produced after pokeweed mitogen stimulation remained positive. Plasma cells in tonsil and in the tissue of peripheral blood of patients with Wladenström's macroglobulinemia were also sometimes Ia-positive although the majority were negative. Studies of membrane IgM and IgD indicated a similar loss in some instances. However, the SIg and Ia antigens were not invariably associated. These results lead to the conclusion that Ia-antigens are differentiation antigens for B cells and are usually lost by the end stage cells in this series.
The influence of ethinyl estradiol (EE) on the effects of dietary cholesterol on the biliary saturation index and on the rate-limiting hepatic enzymes of cholesterol synthesis, hydroxymethylglutaryl-CoA-reductase, and bile acid synthesis, 7 alpha-hydroxylase, were determined. Four groups of 12 male hamsters were treated for 1 month with EE, 15 micrograms per kg per day, or placebo vehicle administered intraperitoneally and fed either a standard diet, 0.8 mg of cholesterol per g of food, or high cholesterol diet, 2.4 mg of cholesterol per g. The high cholesterol diet increased the saturation index to 1.00 +/- 0.03 (P less than 0.01) from 0.65 +/- 0.02 in untreated hamsters on the standard diet. EE treatment on the high cholesterol diet further increased (P less than 0.01) the saturation index to 1.15 +/- 0.02. The high cholesterol diet decreased (P less than 0.01) hydroxymethylglutaryl-CoA-reductase activity from 308 +/- 16 pmoles per mg per min in untreated hamsters on the standard diet. The addition of EE treatment had no effect on hydroxymethylglutaryl-CoA-reductase activity. The high cholesterol diet increased (P less than 0.01) 7 alpha-hydroxylase activity from 23 +/- 1.0 pmoles per mg per min in untreated hamsters on the standard diet. The addition of EE decreased (P less than 0.01) 7 alpha-hydroxylase activity from that in untreated hamsters on the standard diet. The conclusions are as follows: (1) EE prevented dietary cholesterol-induced stimulation of cholesterol 7 alpha-hydroxylase activity; (2) EE enhanced the ability of dietary cholesterol to induce saturated bile; and (3) gallstone formation in estrogen-treated women may result from impaired metabolism of dietary cholesterol.
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A receptor for IgM was demonstrated on the surface of human B lymphocytes by using a rosette technique with ox erythrocytes coated with rabbit IgM antibody (EAM). Lymphocytes forming rosettes with EAM did not bind sheep red cells, had membrane Ia-like antigens and, in some instances, surface immunoglobulin. The specificity of EAM rosettes was confirmed by inhibition experiments with purified human Ig. IgM but not IgG molecules inhibited the rosette reaction. In addition, inhibition of EAM rosettes with IgM fragments showed that the receptor has affinity for a part of the molecule located in the Fc portion. By analogy with the receptors previously found on certain human T cells, receptors for IgM were not detected on freshly isolated B cells, but were expressed after overnight culture in IgM-free media. Studies on different human lymphoid tissues showed that IgM receptors are expressed on a limited percentage of both circulating and noncirculating B cells. In addition to normal B cells, the malignant B cells of a majority of cases of chronic lymphocytic leukemia expressed the receptors for IgM.
Unmeasurable total haemolytic complement (C) was observed in serum of a patient with untreated chronic lymphocytic leukaemia and recurrent non-hereditary angioedema. Analysis of C components immunochemically demonstrated a marked reduction of C1q and C1s inhibitor, undetectable C1r, C1s and an elevated B. Haemolytic C1, C4 and C2 were less than 5 percent of normal, functional C1s inhibitor was absent. Cryoglobulin and C1q precipitins were present in the serum. Of special interest was the presence of high levels of cold-reactive antilymphocyte antibody, determined by both C-dependent cytotoxicity and indirect immunofluorescence. The antibody exhibited specificities for both autologous lymphocytes and lymphocytes from normal donors; cytotoxic activity for autologous leukaemia cells was removed by absorption with normal isologous tonsil lymphocytes. Specific enrichment of this antibody relative to the serum level was demonstrated in the cryoglobulin and its isolated 19S fractions. Free lymphocyte surface antigen was also demonstrated by gel diffusion using specific rabbit antilymphocyte antiserum. These data strongly suggest the presence of pathogenetically significant circulating complexes of lymphocyte surface antigen and specific antibody in certain patients with CLL.
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Human sera were found to contain factors that stimulate and factors that inhibit porphyrin formation by cultured avian liver cells. The capacity of sera to stimulate or inhibit porphyrin formation varied in different hormonal states and in the porphyrias. Sera from 31 post partum women, eight of whom were not lactating, inhibited porphyrin formation to a mean level 30% below the level in control cultures and also inhibited drug and steroid stimulation of porphyrin formation. In contrast, mean porphyrin formation compared to control cultures was increased between 9 and 21% by sera from 52 normal subjects, 16 women on oral contraceptives, and 11 pregnant women. It was increased 193% by sera from nine subjects with acute intermittent porphyria and 172% by sera from 13 subjects with porphyria cutanea tarda. Heated sera or ethanol extracts of sera from all groups of subjects further increased the mean porphyrin stimulation by sera and, for the post partum subjects, eliminated the inhibitory effect. Ethanol extracts of sera from 28 oral contraceptive-treated women caused significantly greater mean stimulation of porphyrin formation than did extracts of sera from 30 normal women. While sera from 17 out of 22 porphyric subjects contained both stimulatory and inhibitory factors, 5 out of 22 had no evidence of an inhibitory component. There appeared to be heterogeneity in the occurrence of the factors among porphyrics.The factor(s) in sera responsible for porphyrin stimulation were heat-stable and insensitive to trypsin; were present in the supernates after ethanol precipitation of plasma proteins; were extractable in ethyl acetate and nondialyzable; and they migrated with the albumincontaining fraction of serum during electrophoresis. The factor(s) responsible for porphyrin inhibition were heat labile, sensitive to trypsin, and resistant to neuraminidase; were present in the ethanol precipitates of sera and were nondialyzable; and they migrated with the gamma globulin fraction of serum during electrophoresis. Inhibition of porphyrin formation was not attributable to heme, free or bound as hemoglobin, hemopexin, or hemalbumin.
Single-stranded DNA (SDNA) occurs in high incidence and in greatest concentration in the sera of patients with systemic lupus erythematosus (SLE), where levels as high as 250 mug/ml were observed. SDNA appears to be an imunogen for anti-SDNA antibodies and forms complexes in vivo of both anti-SDNA-SDNA and anti-NDNA-SDNA types, which apparently play a role in the pathogenesis of the glomerulonephritis found in patients with SLE, SDNA is also found in high incidence but at lower levels in the sera of patients with rheumatoid arthritis. Lesser amounts of SDNA are found in several other diseases in which a low incidence of anti-SDNA antibodies is observed.
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The occurrence of the inappropriate immune response of rheumatoid arthritis is likely controlled by several alleles of class II DR beta chain genes of the major histocompatibility complex (MHC). These include certain of those that encode the serologically distinct DR1 and DR4 specificities. In a manner analogous to a segregation analysis, advantage was taken of ethnic differences in susceptibility associated with different alleles and parallel differences in the organization of the class II haplotypes that specify either similar or divergent serologic specificities. This permitted mapping of this disease susceptibility into a single equivalent polymorphic alpha helical conformation shared by each DR beta allelic product. This suggests that rheumatoid arthritis originates from a unitary immune recognition event initiated by particular class II MHC molecules.
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A solid phase hybridization assay was developed to assess simultaneously the level of transcription of multiple genes in inflammatory tissues and in derivative cell lines. It involves binding of a labelled cDNA probe to plasmids containing cDNAs of the genes of interest in excess concentration applied to a nylon membrane in a dot blot format. After hybridization under stringent conditions, the blot is washed and counts enumerated. Levels of mRNA are compared between different samples by normalization to GAPDH. The results indicate that mesenchymal cells isolated from inflammatory synovia exhibit alterations in the pattern of gene expression which distinguish them from similarly isolated and cultured cells from non-inflammatory synovia. These patterns are sustained through multiple passages in tissue culture, suggesting that this may reflect a persistently altered state of fibroblast differentiation induced by exposure to an inflammatory milieu.