Immunologic Deficiency Diseases Research Articles

Allergy: Principles and Practice.

Volume 1: immunology biology of eosinophils pathophysiology of allergic inflammation physiology pharmacology principles of therapeutics theophylline antihistamines cromolyn and nedocromil antocholinergic agents. Volume 2: clinical science cell-mediated immunity in health and disease immune complexes and allergic disease immunologic deficiency and allergic disease clinical significance of IgE eosinophilia and eosinophili-related disorders development and prevention of allergic disease in childhood asthma - definition and pathogenesis airway hyperresponsiveness pathology of asthma immunotherapy insect allergy anaphylaxis ocular allergy.

HTLV-III/LAV and the Monocyte/Macrophage

Three important articles^1-3in this issue ofTHE JOURNALfocus our attention on infection of monocytes by human T-cell lymphotropic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV), the virus that causes acquired immunodeficiency syndrome. These articles show that a cell with the characteristics of a monocyte/macrophage is the predominantly infected cell in the brain and lung. They provide strong support for the concept that direct viral infection of these organs by HTLV-III/LAV causes central nervous system disease and lymphocytic interstitial pneumonia. Although often overshadowed by devastating immunologic deficiency disease, a high incidence of neurological diseases, characteristically dementia with subacute encephalopathy, has been seen in HTLV-III-infected patients. In the majority of these patients, the neurological diseases were not associated with opportunistic pathogens, suggesting that the neurological disease was caused by the HTLV-III/LAV itself. Convincing evidence of the presence of the virus in the brain was first provided by Southern blot hybridization and

The syndrome of hyperimmunoglobulinemia E and recurrent infections.

The study of immunologic deficiency diseases, although seemingly consuming an inordinate amount of time, energy, and scarce research funds in proportion to the actual number of cases of any given disorder, has nevertheless shed a great deal of light on the normal person's host defense mechanism. Furthermore, considerable amounts of knowledge have spilled over into both closely related and seemingly unrelated fields of medicine from the study of these fascinating cases. Thus, such diverse disciplines as genetics, endocrinology, dermatology, neurology, embryology, nephrology, and the study of metabolism have benefited from a careful dissection of the pathophysiologic mechanisms involved in immunodeficiency states. The article by Brestel and co-workers in this issue (see p 774) is the first to describe the occurrence of a rare, severe bone dysplasia (osteogenesis imperfecta) in association with the syndrome of hyperimmunoglobulinemia E and recurrent infections (Job's syndrome). As they pointed out, disturbances in bone growth have

Development of the concept of immunologic specificity, I

It was evident by the early 1930s that if Paul Ehrlich’s biologic theory of antibody formation was out of favor, his chemical concept of the basis for antibody specificity was very much in vogue (1). The very data that had made the antibody repertoire appear to be too large to be explicable in terms of naturally occurring antibodies almost demanded an immunologic specificity based upon a very precise stereochemical complementarity of configuration between antigen and the putative combining site of the antibody. Indeed, as we have seen, such chemical complementarity of structure was explicitly required by most instruction theories of antibody formation, each of which postulated the existence of some form of template upon which specific configuration might be molded (2). But the work of Landsteiner, on artificial haptens, and of Heidelberger and co-workers, on polysaccharide antigens, accomplished more than this; they signaled to a generation of immunologists that progress in understanding the functions of antibody and the nature of its specificity would only come from chemical approaches to the problem. Nor did biologically oriented immunologists have much to offer at this time in competition to the new trend. Their startling and attractive advances in antitoxic and antibacterial immunity, in novel techniques of serodiagnosis and serotaxonomy, and their important contributions to forensic medicine were mostly a generation in the past; while the discovery of immunologic tolerance and deficiency diseases, of transplantation immunobiology, and of the cellular functions in the immune response would only come with the new biology of a future generation. The occasional development of a new vaccine or the finding of a new blood group thus had little effect upon the growing influence of immunochemistry within the larger field of immunology between about 1920 and 1960 (3). The introduction of more chemical approaches to immunology-of quantitative methods and of approaches to the fine structure of antigens and antibodies-had profound implications for the science of immunology. Not only did it reorient the research goals of a generation of scientists, but it led to the production of impressive amounts of “hard” data that altered the nature of immunologic conceptualization. It is typical of the development of a science that, in its infancy, conceptual advances

Evaluation of children for immunologic deficiency disease.

Evaluation of children for immunologic deficiency disease.

Infections Associated with Immunologic Deficiency Diseases

Infections Associated with Immunologic Deficiency Diseases

Rosette-forming cells, immunologic deficiency diseases and transfer factor.

Abstract Lymphocytes from peripheral blood of normal subjects and of patients with various immunologic deficiency diseases were studied to determine the percentage able to bind with sheep erythrocytes in a formation called a rosette. These rosette-forming cells represent thymus-derived cells. Patients with Nezelof syndrome, Wiskott-Aldrich syndrome, and chronic mucocutaneous candidiasis, all diseases with defects in cellular immunity, had low percentages of these cells. Six patients with acquired hypogammaglobulinemia, a defect in humoral immunity, had normal numbers. Three patients with Wiskott-Aldrich syndrome responded clinically and immunologically to administration of transfer factor, and these patients showed significant increases in rosette-forming cells. One patient with Wiskott-Aldrich syndrome and those with chronic mucocutaneous candidiasis who did not respond to transfer factor did not show increases in rosette-forming cells.

Pneumocystis carinii pneumonia and primary immune deficiency diseases of infancy and childhood

Twenty-nine of 194 cases of <i>Pneumocystis carinii</i> pneumonia in the United States reported to the Parasitic Disease Drug Service over a 3 year period were in children less than one year of age; this attack rate is five times higher than that for any other age group in the general population. Twenty-four of the 29 children had primary immune deficiency disorders. By contrast, acute lymphatic leukemia was the most common disease associated with <i>P. carinii</i> pneumonia in children 1 to 4 years of age (18 to 22 cases). Only one child over one year of age had an immunologic deficiency disease. Severe combined immunodeficiency was the most commonly encountered type of immune deficiency disease (15 of 25 cases). Six (24 per cent) of the patients with immunodeficiencies had at least one sibling with an immunologic deficiency disease who developed proved <i>P. carinii</i> pneumonia in infancy. Although defects in both humoral and cellular immunity appear to be present in these patients, the mode of transmission of <i>P. carinii</i> and its association with immune deficiency states are poorly understood.

Monocyte receptors for immunoglobulin and complement in immunologic deficiency diseases.

SummarySemiquantitative assessment of the human monocyte IgG receptor in normal subjects and patients with acquired agammaglobulinemia, chronic granulomatous disease chronic mucocutaneous candidiasis and the Wiskott‐Aldrich syndrome revealed no detectable differences. The monocyte C3 receptor was found to be normal in cells from patients with the Wiskott‐Aldrich syndrome. Monocyte receptors should be further investigated in patients with various forms of immunologic deficiency.

Immunoglobulin E in Immunologic Deficiency Diseases

Abstract The serum immunoglobulin E concentration was determined in groups of patients with immunologic deficiency diseases that were secondary to a variety of pathophysiologic mechanisms including decreased synthesis, accelerated catabolism and excessive loss of immunoglobulins. The geometric mean IgE level of normal adults was 105 ng/ml with a 95% interval of 5 to 2045. All of the patients with a generalized reduction in immunoglobulin production had a markedly reduced level of IgE. In nine of 10 patients with idiopathic-acquired hypogammaglobulinemia the IgE level was undetectable (i.e., &amp;lt; 4 ng/ml) and was only 5 ng/ml in the remaining patient. Similarly, IgE was undetectable in the serum of seven of eight patients with thymoma and hypogammaglobulinemia and was only 8 ng/ml in the remaining patient. The IgE levels of groups of patients with hypogammaglobulinemia secondary to a shortened immunoglobulin survival were found to be normal in contrast to the markedly reduced IgE levels seen in the patients with a generalized defect in immunoglobulin synthesis. The geometric means of the serum IgE concentrations of the 10 patients with myotonic dystrophy, low IgG concentration and short IgG survival, the two patients with familial hypercatabolic hypoproteinemia and a short survival of many serum proteins, and the 10 patients who had intestinal lymphangiectasia and generalized loss of serum proteins into the gastrointestinal tract did not differ significantly from normal. The 12 patients with Wiskott-Aldrich syndrome had markedly elevated IgE levels with a geometric mean value of 3475 ng/ml. These high IgE levels may reflect chronic stimulation of the IgE synthesizing system by antigens that cannot be processed adequately and eliminated by these patients.

Clinical bone-marrow transplantation workshop.

To the Editor.— A workshop on human bone-marrow transplantation was held at the University of California at Davis on Dec 1, 1971. Attending were those scientists largely responsible for the 133 bone-marrow transplant attempts in 119 patients which have been reported to the American College of Surgeons/National Institutes of Health (ACS/NIH) BoneMarrow Transplant Registry. Complete or partial immunological reconstitution of children with a variety of immunological deficiency diseases was reported. In addition, several cases of successful allogenic bone-marrow grafts were cited in patients with aplastic anemia who had been refractory to previous therapies. Prior to allogenic bone-marrow transplantation, the patients with aplastic anemia received intensive immunosuppressive therapy utilizing antilymphocyte globulin or cyclophosphamide in order to prevent graft rejection. The subsequent demonstration of normal immunological or hematopoietic function plus a donor immunological or hematopoietic marker (eg, a change to donor serum immunoglobulin allotype, donor hematopoietic or lymphoid karyotype, or a change

Clinical Bone-Marrow Transplantation Workshop

To the Editor.— A workshop on human bone-marrow transplantation was held at the University of California at Davis on Dec 1, 1971. Attending were those scientists largely responsible for the 133 bone-marrow transplant attempts in 119 patients which have been reported to the American College of Surgeons/National Institutes of Health (ACS/NIH) BoneMarrow Transplant Registry. Complete or partial immunological reconstitution of children with a variety of immunological deficiency diseases was reported. In addition, several cases of successful allogenic bone-marrow grafts were cited in patients with aplastic anemia who had been refractory to previous therapies. Prior to allogenic bone-marrow transplantation, the patients with aplastic anemia received intensive immunosuppressive therapy utilizing antilymphocyte globulin or cyclophosphamide in order to prevent graft rejection. The subsequent demonstration of normal immunological or hematopoietic function plus a donor immunological or hematopoietic marker (eg, a change to donor serum immunoglobulin allotype, donor hematopoietic or lymphoid karyotype, or a change

Iatrogenic alterations of immunologic surveillance in man and their influence on malignancy.

The surveillance hypothesis of the immunologic control of malignancy has far-reaching clinical implications, of which two major and essentially opposite ones will be considered in this communication. The first concerns the growth of tumors in patients with surveillance failure. From the premise of Burnet (1957, 1963, 1967, 1970) and Thomas (1959), it could have been predicted and was (Thomas 1959, Starzl 1964b, Schwartz et al. 1966) that an increased incidence of de novo tumors would develop in people with naturally occurring immunologic deficiency diseases or in patients whose immune reactivity was deliberately depressed in order to permit their acceptance of organ homografts. The hazard of malignancy consequent to spontaneous deficiency is so well known (Page et al. 1963, Green et al. 1966, Dent et al. 1968, Huber 1968) that it will not be reviewed here. However, the analogous data in iatrogenically immunosuppressed transplant recipients that have accumulated since 1968 will be brought up to date. In addition, some comments will be made about the accidental transplantation of tumors to immunologically depressed humans and about the growth of metastases or residual tumor under these same conditions. The second general topic of this report, and a far more interesting one from a therapeutic point of view, is the expectation that the artificial endowment of immunologic surveillance in a patient whose natural defense system had failed to prevent neoplasia might then have an inhibitory or even destructive effect upon the established growth. Of course, a necessary condition to evaluate this latter possibility is the successful transplantation of immunologically competent tissue such as spleen or bone marrow while at the same time avoiding the kind of fatal graft-versus-host reaction that has defeated essentially all efforts at bone marrow grafting for whatever purpose except between a few HL-A identical siblings. As a first step toward this previously unattainable goal, suggestions will be made for the application to the bone marrow problem of immunosuppressive regimens that have been evolved in the successful transplantation of whole organs such as the kidney, liver, and heart.

Malignancy During Methotrexate and Steroid Therapy for Psoriasis

The concept of immunologic surveillance as a defense against cancer has been proved valid in experimental and clinical studies. A deficiency of the immune system increases the risk of malignancy, as exemplified by the increased tumor incidence found in patients with immunologic deficiency diseases and in immunosuppressed patients bearing renal transplants. A 32-year-old man developed carcinoma with metastases during oral methotrexate and steroid therapy for psoriasis. Immunosuppressive agents are increasingly being used in the therapy for nonfatal disorders and in the prevention of immune rejection of transplanted organs. The probability of increased risk of cancer and spread of metastases in these patients should be evaluated by prospective studies.

Differential inactivation of lymphocytes and bone marrow stem cells by heterologous anti-mouse gamma-globulin serum.

THE principal obstacle to the effective and widespread clinical application of allogeneic bone marrow transplantation, in the treatment of certain immunological deficiency diseases and leukaemia, is the occurrence of graft versus host (GVH) disease1–3. This syndrome, resulting from donor cell-mediated immunological reactions against tissue antigens of the host, probably results from the presence of mature, immunologically reactive cells in the marrow inoculum, derived either adventitiously from, the circulating blood4 or as residents in the marrow. If these reactive cells could be separated out by physical means (compare ref. 5) or be inactivated specifically, still retaining the viability of the marrow stem cells, it should be possible to preclude at will the occurrence of the often fatal GVH disease, following allogeneic bone marrow transplantation.

In vitro lymphocyte response of patients with immunologic deficiency diseases: Rocklin, R. E., Rosen, F. S., and David, J. R.: New Eng. J. Med. 282: 1340, 1970

In vitro lymphocyte response of patients with immunologic deficiency diseases: Rocklin, R. E., Rosen, F. S., and David, J. R.: New Eng. J. Med. 282: 1340, 1970

In vitro lymphocyte response of patients with immunologic deficiency diseases.

Patients with congenital thymic aplasia are unable to manifest delayed hypersensitivity in vivo and in vitro, but usually possess normal levels of immunoglobulins. Patients with X-linked agammaglobulinemia, however, exhibit normal delayed hypersensitivity in vivo, but in vitro studies of lymphocyte transformation have been conflicting. An assay of macrophage migration inhibitory factor, shown to correlate with in vivo delayed hypersensitivity in the guinea pig, has recently been adapted for use in man. This assay shows that lymphocytes from agammaglobulinemic patients with normal delayed hypersensitivity respond to specific antigenic challenge by the production of migration inhibitory factor. However, lymphocytes from patients who fail to manifest delayed hypersensitivity in vivo fail to produce this factor in response to antigenic challenge in vitro. Furthermore, lymphocytes from a patient with congenital thymic aplasia produced the factor after a thymic transplant.

Clinical Aspects of Immunology, ed 2.

This is the second edition of Clinical Aspects of Immunology . The book attempts to cover all major aspects of immunology related to clinical medicine. It is remarkably successful in this effort considering the recent explosion both in research and clinical developments in immunology. The book is divided into five sections. The first is devoted to diagnostic methodology, including techniques for bacterial, viral, fungal, protozoal, and helminth serologic identification, in addition to blood transfusion serology, immunologic aspects of forensic science, and immunoassay techniques. The second section deals with the immune response, the lymphoreticular system, immunoglobulins, and complement. The third portion is concerned with antibody response and activities of immune systems in protection, neoplastic disease, transplantation phenomena and immunologic deficiency diseases. The fourth section reviews the various types of specific hypersensitivity states. Included here are established immune diseases and those associated with abnormal immune responses but with no definite mechanisms established (as

Possible graft-versus-host reaction after intrauterine transfusion for Rh erythroblastosis fetalis.

Abstract An illness characterized by jaundice, aplastic anemia and striking histiocytic reaction in the bone marrow developed in an eight-week-old infant who survived three intrauterine transfusions for Rh erythroblastosis fetalis. Culture of peripheral blood lymphocytes suggested two populations of lymphocytes based on differences in Y-chromosome length. One of these resembled that of one of the donors of the intrauterine blood transfusions. In spite of initial hematologic improvement the infant's condition deteriorated, with multiple infections and progressive weight loss until death at 13 weeks of age. Although lymphoid and thymic atrophy were evident at autopsy these changes were considered to reflect atrophy (secondary to a graft-versus-host reaction) rather than primary immunologic deficiency disease. This observation supports recommendations of others that blood intended for transfusion to the fetus be first rendered free of viable lymphocytes.

Immunologic Deficiency Diseases in Man.

Immunologic Deficiency Diseases in Man.