Immunological analysis in familial common variable immunodeficiency

Immunological and genetic studies were performed in nine members from three generations of the family of a patient with common variable immunodeficiency (CVI). Two additional symptomatic members (mother and grandmother) had CVI. Among other six asymptomatic members, two had CVI and one had selective IgA deficiency. The proportions of monoclonal antibody defined total T cells (Leu 1+), helper phenotype (Leu 3+) suppressor phenotype (Leu 2+) T cells, natural killer cells (Leu 7+) and surface Ig+ B cells and proliferative response to phytohaemagglutinin (PHA), concanavalin A (Con A), pokeweed mitogen (PWM) and in mixed lymphocyte reaction (MLR) were comparable to controls. Addition of purified interleukin-2 (IL-2) resulted in augmentation of PHA-induced proliferation of T lymphocytes similar to that seen in the controls, however with IL-2 freshly isolated T cells in the absence of PHA demonstrated markedly increased proliferative response, suggesting the presence of in vivo activated T cells. Study of HLA phenotype did not reveal any linkage. This study demonstrates the genetic nature, possibly autosomal dominant inheritance, of common variable immunodeficiency; however the immunodeficiency is not linked to any specific HLA antigen.     

Impaired mitogen-induced lymphocyte responses and the hypothalamic-pituitary-adrenal axis in depressive disorders

The lymphocyte stimulation responses to the mitogens phytohemagglutinin (PHA), concanavalin A (Con A) and pokeweed (PWM) were investigated in 30 hospitalized depressed women undergoing a dexamethasone suppression test (DST). Patients were classified according to DSM-III as having major depression with melancholia, without melancholia, and minor depression. The Hamilton Depression Rating Scale (HDRS) and the State-Trait Anxiety Inventory (STAI) were measured. Patients with major depression showed significantly decreased lymphocyte stimulation induced by PHA, Con A, and PWM as compared to those with minor depression. These differences could not be attributed to age, body weight, weight loss, total number of leukocytes, menopausal status, sleep disturbances, concomitant use of low-dosage benzodiazepines or length of drug-free period before testing. The group mean differences in lymphocyte stimulation counts were not affected by the severity of illness or the severity of state and trait anxiety. There were no significant differences in the lymphocyte responses to PHA, Con A, and PWM between DST non-suppressors and DST suppressors. No significant correlations were established between baseline and post dexamethasone cortisol values and the lymphocyte stimulation counts.     

Lymphocyte stimulation and plasma inhibition in patients with malignant neoplasms. A comparative study with three mitogens.

The blastogenic response of lymphocytes from patients with malignant neoplasms was evaluated by stimulation with three phytomitogens (PHA, PWM, and Con A). The response of patient lymphocytes to all three mitogens was significantly lower than that of control lymphocytes, and most patients with abnormal PHA responses also responded abnormally to PWM and Con A. However, a few patients with normal PHA responses were abnormal to Con A, suggesting the suppression of a Con A-sensitive population. The observation that PWM responses were abnormal in patients with lowered PHA lymphocyte stimulation indicates that both T and B lymphocyte mitogen responses were suppressed in these patients. Plasma from patients was capable of either inhibiting or enhancing lymphocyte mitogen stimulation. However, inhibitory plasmas were generally from patients with abnormal mitogen responses.     

Presymptomatic detection and prenatal diagnosis for myotonic dystrophy by means of linked DNA markers.

The close genetic linkage between the loci for apolipoprotein CII (ApoCII) and myotonic dystrophy makes presymptomatic detection and prenatal diagnosis feasible. We report three years' service experience of providing presymptomatic detection and prenatal diagnosis for myotonic dystrophy in 99 families. Careful clinical study of older family members remains important. The introduction of new probes (CKMM and BCL4) has helped to solve the problem of uninformativeness owing to unhelpful genotype distribution in a family. Nevertheless, informativeness cannot be guaranteed and families should be studied before pregnancy is undertaken whenever possible. Presymptomatic testing and prenatal diagnosis for myotonic dystrophy are soundly based. All affected subjects should have DNA banked for future use when other family members may require genotype information.     

Myotonic dystrophy and limb girdle muscular dystrophy in one family

A family is reported in which a 29-year-old woman showed the clinical features of myotonic dystrophy while her 26-year-old brother presented with the clinical picture of limb girdle syndrome. In the affected female, direct genetic testing for the specific myotonic dystrophy mutation on chromosome 19 revealed abnormal expansion of a repeat unit containing the three nucleotides cytosine, thymine, and guanine (CTG) — typical for myotonic dystrophy — while her diseased brother displayed two normal alleles. This supports the hypothesis of the extremely rare occurrence of two clinically and genetically different myopathies in one family. Genetic analysis of six other family members showed that the father of the diseased siblings as well as all of his three brothers and sisters had a pathological CTG repeat expansion, and that the other two family members tested had a normal allelic pattern. The number of CTG repeats in the diseased women was approximately tenfold higher than in her asymptomatic relatives who revealed an abnormal allelic pattern. The increase in CTG repeats with transmission to a subsequent generation in this family was paralleled by a dramatic increase in the severity of myotonic dystrophy.Abbreviations DM myotonic dystrophy - LGS limb girdle syndrome - LGMD limb girdle muscular dystrophy - CTG cytosine, thymine, guanine - PCR polymerase chain reaction     

B Cell Antigens of Black Americans

Fourty-four unrelated North American Blacks and one Black family were tested for B-cell specific antigens with 7th International Workshop antisera. DR specificities were clearly defined in this group, but were generally less frequent than reported for Black Americans in the 7th Workshop report and were most similar in frequency to those reported for African Blacks. Five new B-cell specificities (DuB40-43, 45) were identified. In contradistinction to Caucasians, Black Americans type for HLA-D with homozygous typing cells failed to exhibit strong linkage disequilibrium between D and DR types.     

HLA Frequencies in a Mexican American Population

HLA-A and -B antigens were determined for 300 unrelated Mexican-Americans and 300 unrelated Caucasians from San Antonio by the microlymphocytotoxicity technique, using lymphocytes isolated from freshly drawn peripheral blood. Haplotype frequencies for the Mexican American population were obtained directly, based on family studies, as well as estimated from phenotype data. The results revealed clear differences in the distribution of HLA antigens between Mexican American and Caucasian populations. The predominant HLA specificities in Mexican Americans were A2 and Bw35, while the most frequently observed haplotypes were A2-Bw35, A2-B12 and A2Bw40. Despite the distinct differences in HLA antigen distribution between Mexican American and Caucasian populations, genetic distance values, calculated from the HLA frequencies, were surprisingly low.     

Immunoglobulin levels in dystrophia myotonica.

Levels of immunoglobulins IgG, IgA, and IgM were measured in 38 patients with myotonic dystrophy, in normal members of their families, and in matched controls. Log IgG was significantly reduced in the patients. IgG investigation provides a further parameter to appraise the status of apparently unaffected members of myotonic dystrophy families.     

Seasonal Differences in the Rhythmicity of Human Male and Female Lymphocyte Blastogenic Responses

To test the hypothesis that there are circannual differences in mitotic activity in males and females, normal human peripheral blood lymphocytes were stimulated with suboptimal concentrations of Phytohemagglutinin (PHA), Concanavalin A (Con A) and Poke weed mitogen (PWM) over two summer/winter cycles. Lymphocyte responses for the entire population were significantly higher in the summer than in the winter. The same results were observed when responses were compared between a summer and a successive winter. However, when male and child-bearing age female responses were compared, females showed a higher significant difference for PHA and Con A between summer and winter, but not for PWM. These different responses due to season may reflect a relationship between the neuroendocrine and immune systems. At the cell level, these results suggest that an inherent difference exists between female and male lymphocytes and that these lymphocytes are sensitive to seasonal changes.     

Seasonal Differences in the Rhythmicity of Human Male and Female Lymphocyte Blastogenic Responses

To test the hypothesis that there are circannual differences in mitotic activity in males and females, normal human peripheral blood lymphocytes were stimulated with suboptimal concentrations of Phytohemagglutinin (PHA), Concanavalin A (Con A) and Poke weed mitogen (PWM) over two summer/winter cycles. Lymphocyte responses for the entire population were significantly higher in the summer than in the winter. The same results were observed when responses were compared between a summer and a successive winter. However, when male and child-bearing age female responses were compared, females showed a higher significant difference for PHA and Con A between summer and winter, but not for PWM. These different responses due to season may reflect a relationship between the neuroendocrine and immune systems. At the cell level, these results suggest that an inherent difference exists between female and male lymphocytes and that these lymphocytes are sensitive to seasonal changes.     

Proliferative responses and IL-2 production by mononuclear cells from bovine mammary secretions, and the effect of mammary secretions on peripheral blood lymphocytes.

Mammary gland mononuclear cells (MGM) were compared with peripheral blood mononuclear cells (PBM) for their ability to proliferate in response to phytohaemagglutinin (PHA), concanavalin A (Con A) and pokeweed mitogen (PWM), and to produce interleukin-2 (IL-2) when cultured with Con A. MGM proliferative responses to all three mitogens were at a level only just above background. Following removal of adherent cells by passage of the MGM population over Sephadex G10, their ability to proliferate increased but these responses were still significantly lower (P less than 0.001) than those of PBM. Mammary secretions from non-lactating cows and colostrum, but not milk, were found to suppress the proliferative responses to PHA and Con A of PBM following a 24-hr preincubation period. There was no difference in IL-2 production in response to Con A by Sephadex G10-treated MGM and PBM, and dry-cow secretions had no effect on IL-2 production.     

T lymphocytes in atopic children.

The number of circulating T and B cells and the sensitivity of lymphocytes to stimulation with phytohemagglutinin (PHA), concanavalin A (Con A) and pokeweek mitogen (PWM) was studied in 233 atopic children. The number of T lymphocytes was found to be decreased in cases of rhinoconjunctivitis, asthma as well as atopic eczema. Levels of B lymphocytes were normal. Sensitivity to stimulation with PHA and to a lesser degree, Con A, was significantly decreased whereas stimulation with PWM was unaffected. The severity of the atopic eczema was inversely correlated to T cell numbers. Several lines of evidence indicated that the abnormalities observed were intrinsically associated with the atopic conditions and not evoked by corticosteroid treatment. The results are compatible with the hypothesis that atopy is associated with a defect of a subpopulation of T cells. The possibility that this subpopulation has a suppressor function on reagin formation is discussed.     

Interferon-gamma production by peripheral blood leucocytes from patients with multiple sclerosis and other neurological diseases.

Peripheral blood leucocyte (PBL) cultures of patients with meningoencephalitis, myasthenia gravis, Alzheimer's dementia, Huntington's chorea as well as patients who were recovering from cerebrovascular accidents or from craniotomy for brain tumours, all had defective interferon-gamma (IFN-gamma) responses to stimulation with concanavalin A (Con A) and phytohaemagglutinin (PHA), similar to those already described for PBL cultures of patients with multiple sclerosis. Specifically, cultures from a significant percentage of the patients failed to produce IFN after stimulation with either of the two mitogens. The yields from those cultures that did respond were not significantly lower than those from cultures of healthy blood donors. With increased doses of Con A, the cerebrovascular accident, meningo-encephalitis and MS groups kept their low response frequencies, while the other groups, i.e., myasthenia gravis, Alzheimer's dementia, Huntington's chorea and post-craniotomy, developed an increased response frequency. A good concordance was found between responsiveness to Con A and PHA. With pokeweed mitogen (PWM) as an inducer, no reduction in response frequencies or IFN yields were seen in any of the patient groups. Also, in general, yields were higher with PWM than with Con A.     

Myotonia congenita and myotonic dystrophy in the same family: coexistence of a CLCN1 mutation and expansion in the CNBP (ZNF9) gene

Myotonia is characterized by hyperexcitability of the muscle cell membrane. Myotonic disorders are divided into two main categories: non-dystrophic and dystrophic myotonias. The non-dystrophic myotonias involve solely the muscle system, whereas the dystrophic myotonias are characterized by multisystem involvement and additional muscle weakness. Each category is further subdivided into different groups according to additional clinical features or/and underlying genetic defects. However, the phenotypes and the pathological mechanisms of these myotonic disorders are still not entirely understood. Currently, four genes are identified to be involved in myotonia: the muscle voltage-gated sodium and chloride channel genes SCN4A and CLCN1, the myotonic dystrophy protein kinase (DMPK) gene, and the CCHC-type zinc finger, nucleic acid binding protein gene CNBP. Additional gene(s) and/or modifying factor(s) remain to be identified. In this study, we investigated a large Norwegian family with clinically different presentations of myotonic disorders. Molecular analysis revealed CCTG repeat expansions in the CNBP gene in all affected members, confirming that they have myotonic dystrophy type 2. However, a CLCN1 mutation c.1238C>G, causing p.Phe413Cys, was also identified in several affected family members. Heterozygosity for p.Phe413Cys seems to exaggerate the severity of myotonia and thereby, to some degree, contributing to the pronounced variability in the myotonic phenotype in this family.     

Soluble HLA-II expression in African-Americans

OBJECTIVE: In this study we evaluated the contribution of major histocompatibility complex (MHC) genes to soluble histocompatibility antigen class II (sHLA-II) secretion in African American patients with rheumatoid arthritis (RA). METHODS: A sensitive enzyme-linked immunoassay was used to quantitate sHLA-II in the serum of 7 patients with RA, as well as 28 of their kinships and 49 HLA typed normal African American individuals. RESULTS: Mean sHLA-II values were higher in patients with RA than those in healthy African American individuals (p < 0.05). There were variations in concentrations in individual patients but these were unrelated to any apparent clinical event. The proportion of unaffected family members with detectable levels of sHLA-II was not significantly different than those in normal controls. Neither specific HLA-haplotype, or HLA-allele(s) correlated with high or low sHLA-II secretion. CONCLUSIONS: Our data suggest that sHLA-II molecules are not regulated by MHC linked genes but may be regulated by non-MHC linked genes and racial background may reflect genetic heterogeneity of the expression of this soluble HLA material. These observations contrast with previous observations concerning soluble HLA class I (sHLA-I) molecules in a described population sample which were almost the precise reverse.     

Study of the HLA system in the Haitian population

The HLA-A and HLA-B phenotypes of 329 unrelated Haitian adults were determined and gene and haplotype frequencies were estimated. A summary of the data is presented together with a brief comparison with American Black, American White, and African Black populations. HLA gene and haplotype frequencies of Haitians are quite similar to those for American Blacks. The frequency of Aw34 appears to be smaller in Haitians than in American and African Blacks. No statistically significant differences were found in the frequencies of B-locus antigens.     

The effect of neonatal thymectomy on the ontogeny of mitogen responses in the quokka (Setonix brachyurus)

The lymphocyte responses to phytohaemagglutinin (PHA), Concanavalin A (Con A), and Pokeweed mitogen (PWM) were determined at various intervals throughout pouch life in the quokka (Setonix brachyurus). The responses to both PHA and Con A of lymphocytes from the blood and mesenteric lymph node of thymectomised pouch young were significantly depressed, indicating that these mitogens stimulate thymus-dependent lymphocytes. In contrast to most other vertebrates, splenic leucocytes from intact pouch young responded poorly to stimulation with these mitogens: after neonatal thymectomy the responses were slightly, but not significantly, depressed. Peripheral blood lymphocytes from thymectomised quokkas showed a significantly decreased responsiveness to PWM at 100 and 140 days of age, but the response of lymphocytes from other sources was not significantly different from that of intact animals at comparable ages. There were no significant trends with age in the mitogen responses of lymphocytes from thymectomised pouch young. These data are discussed in relation to the spontaneous restoration of immune responsiveness which occurs after the end of reserves of immunocompetent lymphocytes which had been built up.     

Immunoregulation in experimental filariasis. IV. Induction of non-specific suppression following in vitro exposure of spleen cells from infected jirds to Brugia pahangi antigen.

Studies with inbred jirds chronically infected (greater than 5 months) with Brugia pahangi have demonstrated splenic suppressor cells which modulate in vitro responsiveness to mitogens and parasite antigens. The stimuli which induce suppression were characterized by analysing the effect of activated cells from inbred normal or B. pahangi-infected jirds on the PHA and PWM responsiveness of cultures on normal cells. Regulatory cells were stimulated in vitro with concanavalin A (Con A; 5 micrograms/ml) or an extract of adult B. pahangi (20 micrograms/ml) for 72 hr and irradiated (1500 rads) prior to cocultivation with normal cells. Addition of Con A-activated normal spleen cells to normal cells produced moderate suppression of PHA and enhancement of PWM responsiveness. However, Con A-stimulated spleen cells from infected animals consistently suppressed both the PHA and PWM responsiveness of normal cells by 80-90%. Spleen cells from chronically infected jirds were also induced by B. pahangi antigen to suppress both the PHA and PWM responsiveness of normal lymphocytes. In contrast, spleen cells from animals 3-15 weeks after infection and lymph node cells from all time points were capable of suppressing only PWM responses when stimulated by antigen. Normal spleen cells were not induced by B. pahangi antigens to exhibit immunoregulatory activity. The suppression mediated by antigen-induced spleen cells from chronically infected jirds was partially or totally alleviated by removal of non-specific suppressor cells which are plastic adherent and cyclophosphamide-sensitive, or by removal of antigen-specific suppressor cells which bear receptors for histamine. the results suggest the involvement of regulatory cell circuits in experimental filarial infections.     

Coincidence of neurofibromatosis and myotonic dystrophy in a kindred.

Neurofibromatosis and myotonic dystrophy have occurred in ten members of a nonconsanguineous family with a high degree of concordance. The expression of neurofibromatosis is peripheral, and the expression of myotonic dystrophy has produced at least moderately severe disability. Neither disease has appeared to alter the phenotypic expression of the other when both have occurred simultaneously. Secretor typing supports the assumption that the myotonic dystrophy in this family is the commonly recognised secretor-linked entity. The segregation pattern of the two disorders in this family suggest the possibility of close linkage between the loci for neurofibromatosis and myotonic dystrophy.