Charlotte Cunningham-Rundles

Incidence of cancer in 98 patients with common varied immunodeficiency

Ninety-eight patients with common varied immunodeficiency have been observed for periods of 1–13 years. In 1986, 78 were alive, 19 had died, and 1 could not be located. Eleven patients in the group had developed cancer; two patients had had two cancers. Of the total number of neoplastic malignancies, seven were non-Hodgkins lymphoma, one patient had a Waldenstroms macroglobulinemia, and nine of the patients who developed cancer were female. Cancer developed in the fifth or sixth decade of life for 10 of the 11 patients. These data show an 8- to 13-fold increase in cancer in general for patients who have this immunodeficiency and a 438-fold increase in lymphoma for females.

Intravenous immunoglobulin prophylaxis causing liver damage in 16 of 77 patients with hypogammaglobulinemia or IgG subclass deficiency

Sixteen of 77 patients (21 percent) with common variable immunodeficiency or IgG subclass deficiency contracted non-A, non-B hepatitis in association with intravenous infusions of immunoglobulin. The hepatitis seemed to run a more severe course in these patients than in non-immunodeficient patients. Twelve patients had clinical symptoms, and five died with hepatitis being the cause of death in two and a contributing factor in three. Liver biopsy specimens showed early chronic active hepatitis and cirrhosis. In addition to increases in liver enzymes, 13 patients had increases in alkaline phosphatase levels. All but two patients who contracted hepatitis had been given 50 mg/kg per week or more of intravenous immunoglobulin. Lymphocyte counts, T/B cell ratios, and T-lymphocyte function did not differ between those in whom hepatitis developed and those in whom it did not develop. The hepatitis was associated with more than one batch of a Swedish intravenous immunoglobulin, the immunoglobulin being derived from United States sources as well as from European plasma. Three previous brief reports in the literature have also associated non-A, non-B hepatitis with the intravenous infusion of various immunoglobulins. Biologic materials given to patients, including immunoglobulin, should, whenever possible, be prepared so as to ensure absence of viruses.

Immunoglobulin prophylaxis in patients with antibody deficiency syndromes and anti-IgA antibodies

Sera from three hundred five patients with immunoglobulin deficiencies were analyzed for the presence of anti-IgA antibodies by using indirect agglutination and enzyme-linked immunosorbent assay (ELISA). Anti-IgA antibodies were observed in 15 of 68 (22%) patients with hypogammaglobulinemia and 53 of 185 (29%) patients with selective IgA deficiency, both groups having serum IgA<0.05 g/liter. The highest frequency, 6 of 10 or 60%, was noted for patients with a combined IgA-IgG2 deficiency. No anti-IgA antibodies were detected in 25 patients with serum IgA between 0.05 and 0.27 g/liter and normal amounts of serum IgM and IgG or in 17 patients with hypogammaglobulinemia who had serum IgA of 0.05–0.7 g/liter. The anti-IgA antibodies were primarily of the IgG class, but IgD and IgM anti-IgA were occasionally found. IgE anti-IgA antibodies could not be detected with the presently used technique. The IgG anti-IgA antibodies were mainly of the IgG1 subclass but occasionally also of the subclasses IgG2, IgG3, and IgG4. Of eight patients with anti-IgA antibodies, seven tolerated Ig prophylaxis with a commercial immunoglobulin preparation low in IgA when given either intramuscularly or intravenously. The titers of anti-IgA in the sera of these patients did not rise in relation to the prophylaxis. Only one of the eight patients had a history of previous anaphylactic reactions to IgA-containing blood products. He tolerated six Ig infusions during 5 months with the IgA-depleted preparation without any adverse effects but showed increasing levels of anti-IgA antibodies and ultimately experienced a near-fatal reaction at the seventh infusion.

Interleukin-2 correction of defectivein vitro T-cell mitogenesis in patients with common varied immunodeficiency

We studied the ability of phytohemagglutinin (PHA) and two anti-T-cell monoclonal antibodies, OKT3 and Pan T2, to induce interleukin-2 (IL2) production and proliferation in peripheral blood lymphocytes (PBL) from 14 patients with combined varied immunodeficiency (CVI). The median values of endogenous IL2 produced by mitogen-stimulated PBL was significantly lower in patients than controls irrespective of the mitogen used. The patients, taken as a group, had a significantly decreasedin vitro PBL response to mitogen stimulation when compared to controls. With the addition of a highly purified human IL2 preparation, the proliferative response in the majority of patients was significantly improved with all mitogens. Three patient groups could be distinguished: Group A (3/14) had full restoration of proliferative response with the addition of IL2, Group B (5/14) had partial restoration, and Group C (6/14) had no significant response. The monoclonal antibody, Pan T2, recognized a T-cell proliferative defect in 5 of 14 patients which neither PHA nor OKT3 recognized. This was not significantly corrected by the addition of IL2. This T-cell proliferative defect correlated with the lack of B-cell proliferation and immunoglobulin production in response to B-cell mitogens in three-fourths of the patients assayed. These data show that CVI patients are a heterogeneous group but have in common a decreasedin vitro production of IL2 resulting in a proliferative defect which is correctable at least in part,in vitro, in the majority by the addition of purified IL2.

Intravenous treatment of autoimmune hemolytic anemia with very high dose gammaglobulin.

Abstract. Autoimmune hemolytic anemia (AIHA) has been considered to be unresponsive to intravenous gammaglobulin (IVGG) at the doses that are effective in immune thrombocytopenic purpura and autoimmune neutropenia (usually 2 g/kg total dose). This study reports the use of a higher dose (5 g/kg total dose over 5 days) in four severe cases of AIHA which resulted in a sustained remission in two patients, a transient response in the third, and a failure in the forth patient. These data suggest that larger quantities of IVGG may be needed in this disease, possibly because the reticuloendothelial system appears to be enlarged in AIHA patients.

Defective cellular immune responsein vitro in common variable immunodeficiency

Mononuclear cells from 39 patients with hypogammaglobulinemia of the common variable type were analyzed forin vitro proliferative responses to a panel of cell activators in order to examine the lymphocyte response to mitogens and to study the capacity to generate an immunologically specific secondary response. Patient lymphocyte response to phytohemagglutinin and concanavalin A was found to be significantly lower than that of controls studied in parallel (P<0.01), and low response did not correlate with T-lymphocyte number. Response to pokeweed mitogen was significantly lower than that of controls (P<0.01), but response to zinc, tested in a few patients, was normal. Strong depressions of patient lymphocyte proliferative responses toCandida albicans, Escherichia coli, andStaphylococcus aureus were observed (P<0.01); all of these microbial activators require intact B-cell function for maximum response. Repeated testing of individual patients indicated that poor lymphocyte response could be consistently observed. Examination of changes inin vitro lymphocyte response during clinical course and disease management showed that a consistent pattern of intrinsic lymphocyte functional deficiency could be demonstrated.

Circulating thymic hormone activity in patients with primary and secondary immunodeficiency diseases

Abstract Levels of circulating thymic hormone, facteur thymique serique (FTS), were quantitated in the serum of normal subjects ranging in age from three days to 85 years and in a wide variety of patients with primary and secondary immunodeficiency diseases. FTS levels were low in the serum of a high proportion of patients with common variable immunodeficiency and selective absence or deficiency of IgA. Patients with DiGeorge syndrome always had low levels. In infants with severe combined immunodeficiency (SCID) FTS levels were low in 21 of 23 instances and normal in only two. In patients classified as having primary T-cell deficiency FTS levels were regularly lower than normal as in those with osteopetrosis and ataxia telangiectasia. In patients with Wiskott-Aldrich syndrome and chronic mucocutaneous candidiasis FTS levels were frequently lower than normal. In patients with systemic lupus erythematosus (SLE) FTS levels were below the normal range in the majority of instances, whereas FTS levels within the normal range were characteristic of patients with the X-linked infantile form of agammaglobulinemia (Brutons disease) and patients with progeria. Serums from seven patients were shown to inhibit FTS activity. Of these, serum from six patients with common variable immunodeficiency was studied for its capacity to inhibit synthetic FTS and FTS activity in normal serum. In two of these, FTS activity was inhibited in normal serum, and in five synthetic FTS activity was inhibited. Another patient with immunodeficiency, who had increased IgM levels and neutropenia, also had a serum inhibitor that was active against FTS. Search for an inhibitor of FTS in the serum of individual patients with SCID, chronic mucocutaneous candidiasis and a thymectomized infant revealed no such inhibition. Twenty-seven patients with common variable immunodeficiency were studied for both FTS activity and lymphocytic proliferative responses to phytomitogens and antigens. In 10 of these patients, FTS levels were low and in three of these 10 the responses to both mitogens and antigens were deficient; in four, responses were normal for both, and in three, the responses to antigen were low but the responses to mitogen were normal. In four of 27 patients with low FTS titers, however, an inhibitor against FTS activity was present in their serum, but their proliferative response to mitogens was normal and in two responses to antigens were reduced as well. This finding may explain the frequent dissociation of FTS activity and lymphocyte functions.

Selective IgA deficiency and neoplasia.

Abstract. From the Immunodeficiency Cancer Registry, it has appeared that there is an increased frequency of neoplasia in individuals who have a selective absence of serum IgA. Approaching this question from another point of view, we have found that of 4,120 sera drawn in this cancer‐oriented hospital, 12 sera had a total absence of IgA and 3 additional sera had less than 10 mg/dl. The incidence of IgA deficiency in a cancer hospital is thus 1:342 or 1:273, which is statistically similar to that previously found for other patient groups studied in the USA (average of two studies, 1:418), but it is substatistically increased over the incidence of IgA deficiency found in normal blood donors (average of five studies, 1:1,677). Analysis of these sera by diagnostic categories showed that of 1,517 sera of patients with lympho‐proliferative disorders, 6 were IgA deficient (frequency 1:253), and of 249 sera of patients with gastrointestinal neoplasm, 2 were IgA deficient (frequency 1:125). We conclude that, in the absence of IgA, certain organ systems, the gastrointestinal and lymphoid tissue may be at increased risk for malignant change and that the protective, anti‐neoplastic role of IgA requires investigation.

Zinc deficiency, depressed thymic hormones, and T lymphocyte dysfunction in patients with hypogammaglobulinemia

Abstract Zinc deficient humans and animals have depressed thymic mass and increased susceptibility to infection. In the present studies, we investigated the relationship between cellular immunity, thymic hormones, and serum zinc levels in 19 patients with common varied immunodeficiency. Five (26%) had serum zinc levels 2 SD below normal and 11 (58%) had abnormally low lymphocyte proliferation to at least one mitogen. A significant statistical correlation between zinc levels and lymphocyte proliferation to phytohemagglutinin and concanavalin A was identified. Forty-two percent had abnormally low levels of facteur thymique serique and 74% had low levels of thymopoietin, although no statistical relationship between the levels of these hormones, zinc levels, or lymphocyte proliferation could be identified. Three patients with the most profound zinc deficiency had substantial increases in thymic hormones after zinc repletion, and two had complete resolution of intractable diarrhea. A therapeutic potential of zinc for certain patients with hypogammaglobulinemia is suggested.

T-cell activation defect in common variable immunodeficiency: restoration by phorbol myristate acetate (PMA) or allogeneic macrophages.

Common variable immunodeficiency (CVI) represents a group of familial and sporadic diseases characterized by a range of B-cell, T-cell, and macrophage defects. A defect in T-cell activation, involving reduced proliferation and IL-2 production after stimulation with OKT3 antibody, has been described previously. In the present study we found that these defects could be corrected in vitro by adding phorbol myristate acetate (PMA) to OKT3-stimulated peripheral blood mononuclear cells (PBMC) of 14 patients with CVI. PBMC of 6 out of 7 patients with CVI studied also exhibited a profound defect in IL-2 receptor expression when incubated with OKT3 antibody. IL-2 receptor expression after stimulation with PMA alone was normal, indicating that the OKT3- but not the PMA-induced pathway of IL-2 receptor expression was defective. On the RNA level, the genes for IL-2 and IL-2 receptor were expressed after stimulation with OKT3 antibody. IL-2 and IL-2 receptor gene expression were normal, indicating a possible post-transcriptional defect. To investigate whether the defect in T-cell activation was at the macrophage or the T-cell level, we prepared adherent cells and monocyte-depleted T cells (E+) from 3 patients with CVI and from normal blood donors. Incubating CVI E+ cells with normal adherent cells resulted in normal proliferation and IL-2 production in the presence of OKT3, whereas incubation of normal E+ cells with adherent cells from patients with CVI under the same conditions showed reduced IL-2 production and proliferation, suggesting the macrophage as the origin of the failure in T-cell activation in the patients with CVI studied. Inhibition by macrophage-secreted prostaglandins was excluded by failure to correct the IL-2 production and proliferation defects in the presence of indomethacin.