Normal Numbers Of Lymphocytes Research Articles

IN VITRO AND IN VIVO DEFINITION OF A NEW VARIANT OF SEVERE COMBINED IMMUNODEFICIENCY DISEASE (SCID)

SCID Is a heterogeneous disease caused by at least two known primary defects; specific enzyme deficiency or a defect in thymic epithelial cell maturation. A 12 nonth old male presented with a 7 month history of recurrent fevers, pyogenic infections, and documented Pneumocystis carinii pneumonia. Examination revealed hyperplastic lymphoid tissue. Laboratory data included normal red cell enzymes, normal lymphocyte numbers, profound hypogammaglobulinemia (except for an IgM of 22-47 mg%), no antibody response, but normal numbers of B-cells. 9-15% of his peripheral blood lymphocytes formed E-rosettes; both his PHA and MLR responses were markedly reduced (10% of normal). He did not respond to several skin test antigens or DNCB, and he failed to reject an allogeneic skin graft. Lymph node biopsy demonstrated normal follicle formation, poor germinal center formation, and depletion of cells in the paracortex. Thymus biopsy revealed a large thymus with predominantly E-rosetting cells, PAS-positive epithelial cells, but no Hassall's bodies. Unlike other SCID patients, bone marrow precursor cells were responsive normally to human thymus conditioned medium, suggesting the initial stage(s) of T-cell maturation were achieved in this patient. On the basis of the thymus biopsy and bone marrow precursor cell response, we believe this case of SCID represents a failure of terminal differentiation of intrathymic T-lymphocytes. Supported by Medical Research Council of Canada (MA 4875)

Immunodeficiency in Patients with Non-Hodgkin Lymphomas

Seventy-one previously untreated patients with non-Hodgkin lymphomas were studied with several readilyvailable tests of immune function: number of peripheral blood lymphocytes, serum immunoglobulins, and delayed hypersensitivity to six recall antigens. The results were correlated to histology (Rappaport classification), stage (Ann Arbor classification), the presence of symptoms, and survival. As a group, 38 patients with diffuse lymphomas exhibited marked impairment in reactivity to five of six antigens (p less than 0.03 to p less than 0.001). In addition, lymphopenia and reduced levels of serum IgA were found in association with diffuse histiocytic lymphoma. Among patients with diffuse lymphoma, lymphocyte number and skin test reactivity tended to be greater in those with localized disease or without constitutional symptoms, and survival was superior for patients free of symptoms (p less than 0.01). As a group, 33 patients with nodular lymphoma had normal numbers of lymphocytes, lower levels of serum IgG and IgA, and significant impairment of reactivity to two antigens (streptokinase-streptodornase and mumps; p less than 0.01); reactivity to three other antigens (Candida albicans, coccidiodin, and tuberculin) was normal. Survival for patients with nodular lymphoma was superior (p less than 0.01) compared to those with diffuse lymphomas. In summary, severe immunodeficiency was found in patients with diffuse lymphoma (particularly diffuse histiocytic lymphoma), and definite but much less severe immunodeficiency was characteristic of patients with nodular lymphoma.

Immunodeficiency in patients with non-Hodgkin lymphomas

Seventy-one previously untreated patients with non-Hodgkin lymphomas were studied with several readilyvailable tests of immune function: number of peripheral blood lymphocytes, serum immunoglobulins, and delayed hypersensitivity to six recall antigens. The results were correlated to histology (Rappaport classification), stage (Ann Arbor classification), the presence of symptoms, and survival. As a group, 38 patients with diffuse lymphomas exhibited marked impairment in reactivity to five of six antigens (p less than 0.03 to p less than 0.001). In addition, lymphopenia and reduced levels of serum IgA were found in association with diffuse histiocytic lymphoma. Among patients with diffuse lymphoma, lymphocyte number and skin test reactivity tended to be greater in those with localized disease or without constitutional symptoms, and survival was superior for patients free of symptoms (p less than 0.01). As a group, 33 patients with nodular lymphoma had normal numbers of lymphocytes, lower levels of serum IgG and IgA, and significant impairment of reactivity to two antigens (streptokinase-streptodornase and mumps; p less than 0.01); reactivity to three other antigens (Candida albicans, coccidiodin, and tuberculin) was normal. Survival for patients with nodular lymphoma was superior (p less than 0.01) compared to those with diffuse lymphomas. In summary, severe immunodeficiency was found in patients with diffuse lymphoma (particularly diffuse histiocytic lymphoma), and definite but much less severe immunodeficiency was characteristic of patients with nodular lymphoma.

Chronic cytomegalovirus infection, immunodeficiency, and monoclonal gammopathy-antigen-driven malignancy?

An infant with severe combined immunodeficiency had normal numbers of lymphocytes which bore E rosette and surface Ig markers in an appropriate distribution. However, only minimal responsivity to in vitro stimulation by mitogens and allogenic cells, and none to antigens could be elicited; functional antibody responses were also nil, except to cytomegalovirus. Intrauterine-acquired cytomegalovirus may have caused his immune dysfunction, although the possibility of a postnatal infection cannot be excluded. Therapy with transfer factor and thymus transplantation was unsucessful in restoring immunity and may have aggravated a pre-existing monoclonal gammopathy. It is possible that the monoclonal protein was derived from B-cells transplacentally received from the patients mother.

Defenses against candida infections

We have been particularly interested in matching underlying disease to type of superinfection. It has been stated that leukopenia is associated with Candida superinfection; however, this author does not believe there is evidence that people who have disease induced neutropenia acquire systemic candidiasis. Those acquiring candidiasis generally have had a variety of treatments and neutropenia may be one of the resulting effects; but I know of no epidemiologic data showing that untreated people with any disease which is associated with profound neutropenia have an increased incidence of disseminated infection from Candida or from species of Aspergillus or Mucor. The only two infections that are known to occur with increased frequency in untreated Hodgkin’s disease are tuberculosis and cryptococcosis. For these infections, the evidence seems reasonably good, but the data are less secure for listeriosis, toxoplasmosis, salmonellosis and nocardiosis, since these infections have all been described primarily after the patients with Hodgkin’s disease were under anti tumor therapy. We talk about the susceptibility of patients with, for example, Hodgkin’s disease to acquire superinfections; but often it is not the underlying disease, but their disease, plus what we’ve done to them that makes them susceptible to certain superinfections. Dr. Donald Armstrong (an earlier author in this series) and I examined his experience at Memorial Hospital in New York City; we found that ‘about one half the people acquiring listeria infections in that hospital had low lymphocyte counts before they developed listeriosis.’ This is of interest since Tripathy and Mackanessz6”’ indicate that if the host wishes to handle listeria most effectively a committed lymphocyte and a macrophage that understands the information that it gets from the lymphocytes are necessary. Consequently, the half of the patients at Memorial Hospital who lack the normal number of lymphocytes may have had increased susceptibility to listeriosis because of this. In addition, the patients at Memorial Hospital generally manifested immunoglobulin G deficiency. A study by Njoku-obi and Osebold” indicates that optimal host defense against listeric infections requires not only committed lymphocytes and informed macrophages but also circulating immunoglobulins; in some way that is not clear, these immunoglobulins help in phagocytosis and also in intracellular destruction of the opsonized organisms. Here again, susceptibility to the listeric infection appears to be predicated upon underlying lymphocytic malignancy plus host modification by therapy. In the leukemic patient, the organisms causing most of the trouble among the fungi are species of Candida. Why are such patients inordinately susceptible to these particular yeasts? The data suggest that antibiotics, steroids, anti leukemia agents, neutropenia and direct access for the organism to the blood stream all act in concert to promote Candida. In this regard, the evidence is beginning to accumulate that the scalp vein needle is less dangerous than the intravenous catheter by about ten-fold in terms of the proclivity for superinfections.’ A prospective study by Curry and Quie’ on the use of hyperalimentation by intravenous catheter showed that 27% of individuals so treated developed bacteremia or fungemia,

IgA DEFICIENCY, EPILEPSY, AND PHENYTOIN TREATMENT

In a prospective study of thirty-two children with seizures treated with phenytoin (diphenylhydantoin), five had low levels of serum-IgA before treatment. All of these were among the fifteen who had had febrile convulsions in infancy. IgA levels fell significantly during 6 months treatment in the fourteen patients studied sequentially. Treated children with low serum-IgA had normal numbers of lymphocytes with surface IgA. This suggests that phenytoin causes failure of terminal differentiation of B lym phocytes, and is the first known cause of this, the commonest mechanism of immunoglobulin deficiency.

IMMUNOGLOBULINS ON THE SURFACE OF LYMPHOCYTES

Immunofluorescent studies using live cells from antibody-forming organs and anti-immunoglobulin antibodies demonstrate two populations of small lymphocytes which are differentiated by the presence or absence of Ig on their surface membranes. Most of the lymphocytes with detectable surface Ig appear to derive from cells of the bone marrow, while most of the Ig-negative lymphocytes derive from the thymus. Thus, adult mice thymectomized, lethally irradiated, and transplanted with bone marrow cells showed a normal number of lymphocytes with surface Ig but were depleted of the Ig-negative lymphocytes. Injection of thymocytes into these mice did not result in an increase in the number of lymphocytes with surface Ig in spleen and lymph nodes. Most of the injected thymocytes could be identified by means of histocompatibility markers. Also, the spleen and lymph nodes of neonatally thymectomized mice contained lymphocytes with surface Ig but were depleted of the Ig-negative lymphocytes. Attempts were made to identify light chains on thymocytes by a sensitive radioimmunoassay. In some experiments no light chains were detected and in others a small amount, i.e. no more than 2.6% of the amount present on spleen lymphocytes, could be detected. Whether these low figures are significant or represent a small amount of serum contamination is not clear as yet.

CONTROL OF LYMPHOCYTE LEVEL IN THE BLOOD

This hypothesis proposes: (1) that small lymphocytes carry a recognition site on their surface; (2) that detection of lymphocytes carrying this recognition site (possibly during migration across the endothelium of the post-capillary venule) inhibits lymphocyte proliferation, thus maintaining normal numbers of lymphocytes; (3) that the recognition site is identical with the phytohæmagglutinin-responsive site and is closely associated with sites reacting with specific antigens; and (4) that the recognition site is lost or blocked in chronic lymphocytic leukæmia and in some of the lymphomas.

Lymphocytes from thymectomized rats: immunologic, proliferative, and metabolic properties.

Thoracic duct lymphocytes from neonatally thymectomized Lewis rats fail to produce runt disease in newborn Brown Norway rats when injected with up to ten times the number of normal lymphocytes needed to cause runting. The immunologically deficient lymphocytes appear, however, to confer tolerance, and at least some enlarge and divide when stimulated in vitro with phytohemagglutinin, or xenogeneic or allogeneic cells. Small lymphocytes from thymectomized animals have defective RNA metabolism as judged by a marked impairment in their ability to incorporate uridine-5-H(3) or cytidine-H(3) in vitro.

PRESENCE OF PLASMA CELLS AND γ1M-GLOBULIN SYNTHESIS IN A PATIENT WITH THYMIC ALYMPHOPLASIA

A child is described who had thymic alymphoplasia with increased serum concentrations of γ1M-globulins and a deficiency of γ1A- and 7S γ2-globulins; the child was subject to severe infections from 2 weeks of age and succumbed to pneumonia at 11 months of age. Even though the tissues of this patient at necropsy revealed a remarkable paucity of lymphocytes, there were relatively normal numbers of lymphocytes in his peripheral circulation and his bone marrow. Plasma cells were readily demonstrated in the spleen and lymph nodes. The studies suggest that the development of plasma cells and γ1M-globulin synthesis may occur independently of the development of the thymus and the small lymphocytes in man.

THE THYMUS AND OTHER LYMPHOID TISSUES IN CONGENITAL AGAMMAGLOBULINEMIA

Patients with congenital agammaglobulinemia may be separated clinically and pathologically into two groups. One group manifests a persistent lymphopenia and is characterized clinically by an unremitting course marked by pneumonia, moniliasis, and other infections usually beginning in the first three months of life and, thus far, terminating fatally during the patient's infancy. These patients have thymic alymphoplasia and lymphocytic hypoplasia of their tissues: the thymus is rudimentary, and the other lymphoid structures contain only sparse populations of small lymphocytes. The thymic alymphoplasia and general deficiency in small lymphocytes appear to be inherited characteristics and the evidence suggests that the primary defect is thymic alymphoplasia which results in generalized lymphocytic hypoplasia including lymphopenia. The second group of patients often has a later onset and a more intermittent course of bacterial infections, a variable leukocyte response marked only occasionally by transitory lymphopenia; their lymphoid organs including the thymus contain more nearly normal numbers of lymphocytes. Plasma cells and germinal follicles are absent from the tissues of both groups of patients, but the marked generalized paucity of small lymphocytes in these patients with thymic alymphoplasia results in an increased susceptibility to infection beyond that seen in nonlymphopenic agammaglobu-linemia. Whatever the exact contribution of the small lymphocyte to resistance to infection, it appears to be significant and its loss is not replaced by γ-globulin therapy.