Reversible dysfunction of T-lymphocytes in common variable immunodeficiency.

A 30-year-old man with recurrent sinopulmonary infections, eventually fatal, was found to have common variable immunodeficiency. In addition to low serum immunoglobulin concentrations he also had lymphopenia and cell-mediated immunodeficiency as shown by cutaneous anergy and a poor lymphocyte response to phytohemagglutinin (PHA) in vitro. However, intradermal injection of PHA produced a vigorous cutaneous response, showing that some cell-mediated responsiveness remained. The responsiveness of his lymphocytes to PHA was restored towards normal (confirmed by chromosome studies) by the addition of a small number of normal leukocytes to cultures; thus a reversible functional defect in his T-lymphocytes was revealed. Experiments indicated that the defect was cellular and not due to serum factors and it was concluded that normal leukocytes restored a missing factor to the patient''s T-lymphocytes. Although counts of macrophage precursor cells in the bloodstream were low, thus contributing to the immunodeficiency, this could not have caused the reduced PHA response. Several relatives of this patient had lymphoma; two cousins had common variable immunodeficiency.     

Thymopoietin-induced acquisition of responsiveness to T cell mitogens

A population of murine spleen cells, enriched by flotation in discontinuous bovine serum albumin gradients, was induced to differentiate in vitro by incubation with the purified thymic polypeptide hormone thymopoietin. These cells, normally unresponsive to both T and B cell mitogens, acquired the capacity to respond to the T cell mitogens concanavalin A (Con A) and phytohemagglutinin (PHA) but remained unresponsive to the B cell mitogen lipopolysaccharide from Escherichia coli. The acquisition of responsiveness to mitogens was not impaired by treatment with anti-Thy-1 serum + complement before induction but was prevented by this treatment after induction; thus the cells acquiring the functional capacity to respond to T cell mitogens had also been induced to express the T cell alloantigen Thy-1. Like the expression of T cell alloantigens, the capacity to respond to Con A developed rapidly and reached its maximum within 6 hr. Responses to Con A always greatly exceeded those to PHA. Our data suggest that committed precursor cells, which we believe to be prothymocytes, are induced by thymopoietin to differentiate to cells with an antigenic phenotype and mitogen responsiveness similar to cortical thymocytes.     

Thymocyte-stimulating factor from peripheral blood cells.

Human peripheral blood leukocytes (HPBL) produce a thymocyte-stimulating factor (TSF-HPBL) that enhances the phytohemagglutinin (PHA) and concanavalin A (Con A) responsiveness of murine thymocytes. This activity is considerably specific for thymocytes. TSF-HPBL is not mitogenic by itself. Experiments with cell cultures pretreated with carbonyl iron particles showed that phagocytic cells are not involved in the production of mouse and rat TSF but are involved in the production of TSF-HPBL. The dose-response profile to PHA of murine thymocytes cultured in the presence of TSF-containing supernatants is similar to that of mature, immunocompetent spleen cells. TSF-HPBL, however, does not enhance the PHA responsiveness of murine thymocytes at low (<0.25 μg/microwell) concentrations of mitogen. TSF enhances the PHA and Con A responsiveness of the high-density subpopulations of thymocytes isolated on a Ficoll-Hypaque gradient. In general, the enhancing effect of TSF-HPBL on these subpopulations of thymocytes is smaller than that exerted by TSF. While supernatants containing TSF confer to thymocytes the ability to participate in a mixed lymphocyte reaction, this effect is not exerted by supernatants containing TSF-HPBL. A factor enhancing the PHA and Con A responsiveness of murine thymocytes is also produced by murine peripheral blood leukocytes (TSF-MPBL). This factor, similarly to TSF-HPBL, is produced by phagocytic cells and does not confer to murine thymocytes the ability to participate in a mixed lymphocyte reaction. Human T-cell lines do not enhance the PHA or Con A responsiveness of murine thymocytes. TSF-HPBL has a molecular weight of about 30,000 daltons, as measured by Sephadex filtration. Its half-time of inactivation as 56 °C is 162 ± 8 min.     

Lytic,nontransforming Epstein-Barr virus (EBV) from a patient with chronic active EBV infection.

A new wild-type isolate of Epstein-Barr virus (EBV) was identified in follow-up studies of a case of chronic active EBV infection in an 8-year-old girl who had high titres of antibody to viral capsid antigen and early antigen (EA) (greater than 20 480 and 2560 respectively), persistent splenomegaly and abnormal immunologic features. More than 10 throat washings from this patient failed to transform cord blood lymphocytes (CBL), but at least 7 were able to induce EA in Raji cells. Supernatants from cultures of the lymphoblastoid cell line obtained by in-vitro infection of this patient''s leukocytes with the B95-8 strain of EBV revealed a herpesvirus particle when examined by electron microscopy. The same supernatants were unable to transform CBL but could induce EA in Raji cells upon superinfection. In 30 or more trials the patient''s lymphocytes never transformed spontaneously but did become positive for EBV nuclear antigen and EA in the first week of culture at least twice. Parallel studies performed on the father of the patient yielded similar results. This, then, is the first report documenting lytic activity associated with a wild-type EBV isolate.     

Dipetalonema viteae: Response of spleen cells in experimental mouse filariasis to mitogens and antigens

Balb/c mice were infected by transplanting 3, 5, 10, or 20 female adult Dipetalonema viteae under the dorsal skin. The microfilaremias resulting from infections with 3 or 5 adult worms were of lesser magnitude and of shorter duration than those produced in infections with 10 or 20 worms. Spleen cells taken from these mice at various intervals after infection were assayed in vitro for their ability to respond to phytohemagglutinin (PHA) or lipopolysaccharide (LPS). There was no depression in the response to LPS or to PHA in mice given infections of 3 or 5 D. viteae adult worms. In contrast, the response to PHA was significantly depressed in groups receiving 10 or 20 adult female worms 12 days after infection and by Day 25, the depression was severe. Thereafter the PHA responsiveness recovered gradually to reach control values on Day 60. In mice transplanted with 10 or 20 D. viteae adult worms there was no significant depression in the response to LPS at any time during the infection, but the response was increased slightly sporadically during infection. These results indicate that in mice, this infection causes an initial suppression in the function of PHA-sensitive T cells but has little effect on the B cells which respond to LPS. A factor present in serum taken on Day 25 from mice infected with 10 or 20 adult worms inhibited the proliferative response to PHA by spleen cells from normal mice. The recovery of PHA responsiveness in mice given the heavier infections coincided with death of the adult worms, but mitogen reactivity and microfilaremia were unrelated. Antigens from male or female worms induced cell division in spleen cells taken from infected mice after microfilaremia had ceased whether they were implanted with 3 or 10 adult worms.     

Depression of mitogen response in spleen cells from reticuloendotheliosis virus-infected chickens and their suppressive effect on normal lymphocyte response

Spleen cells and peripheral blood lymphocytes from chickens infected with reticuloendotheliosis virus (REV) were depressed in their responsiveness to phytohemagglutinin (PHA). When spleen cells from uninfected chickens were co-cultured with spleen cells from chickens infected with REV at 2 weeks of age, the PHA response by the normal cells was completely suppressed. Although spleen cells from chickens infected with REV at 6 or 9 weeks of age were also suppressed in their ability to respond to PHA, they did not suppress the mitogenic response of normal cells in mixed cultures.     

Serial immune testing in surgically resected lung cancer patients

Summary Immunoregulation of phytohemagglutinin (PHA) responsiveness by glass-adherent cells and prostaglandin-synthesizing cells was serially monitored in the peripheral blood mononuclear cells (PBMC) of surgically resected stage I and stage II lung cancer patients entered on a trial of adjuvant immunotherapy. The relationship between immunoregulatory cell function, immunocompetence, and disease relapse was determined. Immunoregulatory activity was measured in PHA-stimulated cultures in the presence and absence of 2 g/ml indomethacin and in the presence and absence of glass-adherent cells. In each instance of disease relapse seen, an increase in immunoregulatory cell function to a level significantly different from normal was observed 3 months prior to or coincident with clinical confirmation of disease recurrence. This was usually associated with a decline in PHA responsiveness. In the patients who did not relapse, the levels of PHA responsiveness and immunoregulatory function persisted within normal limits throughout the course of study. Percentages and numbers of leukocytes and leukocyte subsets and delayed cutaneous hypersensitivity were also monitored in this study, but could not be consistently correlated with early changes in clinical disease status. These data suggest that the development of indomethacin-sensitive and glass-adherent suppressor cells may precede and predict for tumor recurrence in surgically resected lung cancer patients.     

Antibody that blocks stimulation of cortisol secretion by adrenocorticotrophic hormone in Addison's disease

To investigate whether Addison''s disease may in some cases be due to the blocking of adrenocorticotrophic hormone''s action at the adrenal cortex by antibodies IgG isolated from a woman with Addison''s disease associated with the autoimmune polyglandular syndrome type I was studied. Its effects on guinea pig adrenal cells in vitro were investigated and compared with those of IgG from three normal subjects and IgG obtained commercially. IgG from the patient inhibited the stimulation of cortisol secretion by adrenocorticotrophic hormone by 77 (SD 2)% and 57 (12)% at concentrations of 0·5 and 0·05 g/l, respectively; IgG prepared five months after she had started treatment with replacement steroids inhibited cortisol secretion by 74 (1)% (0·5 g/l) and 51 (15)% (0·05 g/l). The other IgGs had no inhibitory effects. The IgG from the patient and that obtained commercially did not inhibit the stimulation of cortisol secretion by dibutyryl cyclic adenosine monophosphate or precursors of cortisol. None of the IgGs bound to adrenocorticotrophic hormone.These results suggest that the IgG from the patient acted against the receptor for adrenocorticotrophic hormone, and its presence may explain the patient''s raised concentrations of adrenocorticotrophic hormone, failure to respond to exogenous adrenocorticotrophic hormone, and normal basal cortisol concentrations. Addison''s disease may thus in some instances be a receptor antibody disease.     

Phylogenetic studies on T cells. I. Lymphocytes of the shark with differential response to phytohemagglutinin and concanavalin A

Peripheral blood lymphocytes of the nurse shark (Ginglymostoma cirratum) respond to stimulation by concanavalin A (Con A) as evidenced by increased incorporation of tritiated thymidine. Separation by means of Ficoll-Isopaque yields two or more bands and a sediment, all of which contain lymphocytes responsive to Con A. Only the bottom cells react to phytohemagglutinin (PHA). This reaction cannot be detected in the unseparated lymphocyte population. Thus, only a unique subset of lymphocytes appears to be responsive to PHA and is probably blocked in its response by other cells. The findings suggest that differentiation toward Con A responsiveness may have preceded phylogenetically the responsiveness to PHA. Judging by the requirement for high concentrations of both mitogens the receptor sites on shark lymphocytes appear to be present in lower densities than on lymphocytes of higher vertebrates.     

Hormonal stimulation and paternal experience influence responsiveness to infant distress vocalizations by adult male common marmosets,Callithrix jacchus

Parental experience and hormones play a large role in the common marmoset (Callithrix jacchus) father's care of their offspring. We tested the effect of exogenous estradiol or testosterone on the responsiveness of common marmosets to respond to infant distress vocalizations and whether males who haven't become fathers yet (paired males) would have increased responsiveness to infant distress calls with either steroid or whether parental experience is the most important component for the onset of paternal care. Sixteen male marmosets (8 fathers, 8 paired males) received a vehicle, low dose or high dose of estradiol and additional 16 males were tested with testosterone at three doses for their response either to a vocal control or a recording of an infant distress call for 10 min. Without steroid stimulation fathers were significantly more likely to respond to the infant distress stimulus than paired males. Low dose estradiol stimulation resulted in a significant increase in fathers' behavioral response towards the infant distress stimulus but not in paired males. Fathers also showed a significant increase in infant responsiveness from the vehicle dose to the estradiol low dose treatment, but not to the estradiol high dose treatment. Testosterone treatment did not show significant differences between infant responsiveness at either dose and between fathers and paired males. We suggest that neither steroid is involved in the onset of paternal care behaviors in the marmoset but that estradiol may be involved in facilitating paternal motivation in experienced fathers.     

Effects of living with and looking after survivors of a stroke.

Information from a two year, longitudinal study on a community sample of patients with acute stroke was analysed to determine the effects of the stroke on the mood of the chief carer (the person living with the patient). Increased anxiety was the most commonly reported change six months after stroke. Significant depression was seen in 11-13% of carers over the first two years after stroke. The patient''s functional disability was associated with depression in the carer over the first year but not at two years. A perceived poor recovery by the patient, a low level of general activities by the patient, and depression in the patient were also associated with depression in the carer within the first year. At two years after stroke none of the measured factors were related to a carer''s level of depression. Carers of patients who have suffered stroke showed anxiety and emotional distress unrelated to the patient''s physical disability after two years. More help from stroke support groups for carers is perhaps needed.     

Expression and modulation of C3 receptors during early T-cell ontogeny.

Using a corosette assay, optimal conditions were established for the detection of C3 receptors on T lymphocytes. E⁺-C3⁺ corosetting cells were demonstrated in four T-cell lines and six patients with E-rosetting acute lymphoblastic leukemia. Small numbers were detected in normal lymphoid tissues whereas thoracic duct lymph contained a large number of these cells. Following incubation of these tissues with thymic humoral factors, there was a decrease in corosetting cells with an increase in cells rosetting SRBC exclusively. Similar results were observed in vivo in a patient with severe combined immunodeficiency following a thymic epithelial cell transplant. Our data suggest that C3 receptor-bearing T lymphocytes occur early in T-cell ontogeny and can be modulated by thymic humoral factors.     

青少年GATA2缺陷继发骨髓增生异常综合征一例并文献复习

摘要 目的：提高对青少年GATA2缺陷继发骨髓增生异常综合征（MDS）疾病的认识。方法：回顾性分析我院收治的1例青少年GATA2缺陷继发MDS患者的诊疗过程,并结合相关文献进行复习总结。结果：患者男,17岁,2018年6月于我科诊断为MDS(MDS-EB-I,IPSS中危-1;WPSS高危;IPSS-R高危),继发骨髓纤维化。完善血液遗传全外显子基因检查提示患者GATA2基因突变。修正诊断为GATA2缺陷综合征、继发MDS( MDS-EB-I,IPSS中危-1;WPSS高危;IPSS-R高危) 、继发骨髓纤维化。完善患者姐姐血常规检查提示白细胞轻度减少,检查患者姐姐GATA2基因检测到GATA2基因错义突变。患者治疗期间反复出现多部位感染。进一步检查患者父母GATA2基因提示患者父亲GATA2基因存在错义突变。患者GATA2基因突变系父系遗传。结论：对于青少年MDS患者,应对其进行血液遗传学全外显子基因检查以确认其有无先天性疾病;对于存在先天性基因突变的患者,建议行家系筛查,并尽早行造血干细胞移植治疗。     

Lymphocyte transformation in casein-induced murine amyloidosis.

Spleen lymphocytes from casein-induced amyloidotic mice demonstrate diminished transformation in vitro to PHA-P, concanavalin A, and pokeweed mitogen but a normal response to lipopolysaccharide. Thymic and peripheral blood lymphocytes respond normally to these mitogens. The amyloidogen casein acted as a mitogen in both normal and casein injected mice. The diminished PHA responsiveness of spleen lymphocytes in vitro could have resulted from an inhibitory effect of amyloid fibrils on lymphocyte proliferation and did not indicate a generalized diminished cellular immunologic responsiveness of amyloidotic mice.     

Findings of negligence followed communication lapses in BC aneurysm case

Negligence is sometimes established on the basis of lapses in communication and patient care management that, in hindsight, could have been avoided. A recent BC court case concerned a patient who died because of a ruptured aneurysm. A Supreme Court judge found that some of the physicians involved had failed in their duty to diagnose the patient''s condition properly, or failed to communicate to one another significant signs of the patient''s illness, and failed to refer him in time to the medical specialists who could have diagnosed and treated his condition promptly.     

Studies on the mitogen responses of germfree allogeneic chimeras. II. Maturation of two cell types and partial restoration of responsiveness of the short-term chimeras.

Germfree allogeneic bone marrow chimeras (ABMC) were produced by the i.v. injection of approximately 10(7) bone marrow cells from germfree DBA/2 mice into lethally irradiated germfree C3H mice. In the germfree state, the short-term ABMC showed no histologic signs of graft-vs-host reactions (GVHR), yet splenic lymphocytes were unable to respond to PHA, Con A, or SRBC. Attempts to remove responsiveness by the implantation of a DBA/2 thymus under the host kidney capsule also resulted in failure. However, when the donor thymus was enclosed in a cell-impermeable chamber to eliminate a GVH reaction, responsiveness to Con A was restored. The PHA and SRBC responses were unaffected by this treatment. Daily injections of thymosin caused both an increased Con A response and increased numbers of PFC, although the PHA response was again unaffected. Thus, soluble substances from thymic tissue can be used to overcome partially the histocompatibility barrier present in the ABMC that affects at least two different functional cell populations.     

Report of a patient with T-cell deficiency and normal B-cell function: A new immunodeficiency disease with response to transfer factor

An 11-yr-old boy had recurrent fevers and pulmonary infections since early childhood and, at age 7, had disseminated varicella with bilateral pneumonitis. A female sibling, age 1, died during this period of time with varicella pneumonia. Two years later, an immunological evaluation showed severe deficits in cellular immunity with skin anergy and very low or poor in vitro lymphocyte proliferative responses to mitogens, allogeneic cells and specific antigens. Quantitation of peripheral T-cells by spontaneous rosette formation was also low—40–45% (normal 61%). On the other hand, B-cell immunity seemed to be completely normal. Serum immunoglobulins and the immunoglobulin receptors on peripheral lymphocytes were normal. The patient produced specific antibodies upon antigen challenge (immunization) and after natural infection. Following transfer factor therapy, conversion of skin reactivity and clinical improvement occurred. No changes were seen in in vitro lymphocyte function with transfer factor therapy. Immunologic reconstitution persisted for 6 mo, after which the patient responded again to the administration of transfer factor. Although this patient has several characteristics in common with Nezelof's syndrome, the patient described in this report appears to represent a distinct clinical entity of primary isolated T-cell deficiency and normal B-cell immunity. The normal B-cell immune system, and the clinical and immunological response to transfer factor therapy, differentiates our patient from the syndrome of thymic dysplasia with immunoglobulin synthesis (Nezelof's syndrome).     

Immunologic reconstitution, autoimmunity, and T-cell immune deficiencies.

A 17-month-old female with combined immunodeficiency, a proliferative response to allogeneic cells in MLC, and circulating B lymphocytes (50%, all with surface immunoglobulin M) was treated with transfer factor (TF). After six doses of transfer factor, serum levels of IgG increased from 234 mg/dl to 1071 mg/dl and a lymphocyte proliferative response was detected to pokeweed mitogen. However, no change in T-cell function was observed. Clinically, she did well, but after the eighth dose of transfer factor, she developed the nephrotic syndrome. Renal biopsy suggested immune complex glomerulonephritis. Subsequently following treatment for Pneumocystis carinii, a 20-day cultured thymus was transplanted intraperitoneally. Two weeks after thymus transplant, the patient started to develop delayed skin reactivity and in vitro mitogen responsiveness. Six weeks posttransplant, the PHA and pokeweed mitogen responses were approximately 60% of normal, but the Concanavalin A response had disappeared. Subsequently she developed a Coombs positive hemolytic anemia, a cutaneous vasculitis, and thrombocytopenia. There was no evidence of GVH disease. Multiple autoimmune manifestations developed in association with transfer factor therapy and transplantation of cultured thymus tissue. T-Cell deficiencies are predisposed to autoimmune diseases because of imbalances of regulatory T-cell function. These imbalances of regulatory T-cell function may occur especially following partial immune reconstitution. The changes in B-cell function during transfer factor therapy may have resulted from enhanced T-cell-B-cell interaction. This immunopotentiation effect of transfer factor together with partial T-cell reconstitution may have led to B-cell hyperresponsiveness and autoimmune disease.     

PSYCHOTHERAPY OF ALCOHOLICS—The Concept of Psychotherapeutic Motivation

The psychiatric patient''s compliance with requirements of therapy (attendance, responsiveness, verbalization, etc.) often is adopted by the therapist as the chief criterion of motivation for cure. By these standards alcoholics often are judged to be poorly motivated and unsuited to the therapist''s mode of therapy. In such cases, the method may have to be adapted to the case, and a more permissive attitude taken toward the patient''s apparent noncooperation.     

Quinine-induced agranulocytosis: toxic effect of quinine bisulphate on bone marrow cultures in vitro.

In a case of quinine-induced agranulocytosis marrow culture studies confirmed the inhibitory effect on the patient''s cells of equivalent therapeutic plasma concentrations of quinine. Similar concentrations had no effect on normal marrow cells. Quinidine, the stereoisomer of quinine, had no effect on either cells from the patient or normal cells. The results encourage the use of in-vitro bone marrow cultures for identifying drugs responsible for agranulocytosis.