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C Cunningham-Rundles

Publications and source records attributed to C Cunningham-Rundles.

At least 19 recordsLinked to original sources
PubMed2001

Long-term low-dose IL-2 enhances immune function in common variable immunodeficiency.

Common variable immunodeficiency (CVID) is a primary immunodeficiency disease characterized by hypogammaglobulinemia and lack of antibody production. Numerous T cell defects have been described, including reduced gene expression and production of IL-2. Since some of the T cell defects could be explained by lack of IL-2, we have been investigating the effects of in vivo IL-2 treatment. Here, a long-acting form of IL-2, PEG-IL-2, was given for 12-18 months to 15 randomly chosen CVID subjects, in comparison to 39 CVID subjects who served as controls. After 6 to 12 months of treatment, T cell proliferative responses to mitogens and to IL-2 were significantly enhanced; proliferative responses to tetanus and candida antigens increased up to 50-fold. Four of eight subjects immunized with the neoantigen bacteriophage φX 174 displayed increased antibody responses after treatment. Treated subjects recorded reduced, but not overall statistically significant, days of bronchitis, diarrhea, and joint pain. These data indicate that IL-2 might serve as an adjuvant to therapy in some subjects with CVID, enhancing T cell functions and reversing T cell anergy in most.

Adolescent↗
PubMed2001

Unmasking of acquired autoimmune C1-inhibitor deficiency by an angiotensin-converting enzyme inhibitor.

BACKGROUND: A majority of angioedema arise from unknown etiologies. Angioedema may also arise from medications or deficiency of C1-esterase inhibitor (C1-INH); either of these may lead to recurrent, sometimes life-threatening attacks of subcutaneous or submucosal edema if the angioedema involves the tongue, throat, or larynx. We describe a patient with unknown acquired C1-INH deficiency, who experienced only mild attacks of angioedema before treatment with an angiotensin-converting enzyme (ACE) inhibitor. This therapy led to life-threatening respiratory distress. OBJECTIVE: To investigate this patient's life-threatening angioedema. METHODS: Serum protein electrophoresis and immunofixation were performed. The titer of anti-C1-inhibitor autoantibody was determined by ELISA, and the specificity of the autoantibody demonstrated by using purified C1-INH to block binding in the ELISA. Finally, fractions from the immunoelectrophoresis gel were tested for C1-INH autoantibody by ELISA. RESULTS: Complement activation was documented by reduced C1-INH, C1q, and C4, and the patient was found to have an autoantibody of IgG2 isotype specific for C1-INH. After discontinuation of the ACE inhibitor, he continued to have decreased C1-INH and positive C1-INH autoantibodies. CONCLUSIONS: This case describes a patient who had a history of mild facial and extremity swelling with abdominal symptoms before ACE inhibitor treatment; this medication resulted in life-threatening respiratory distress. The use of the ACE inhibitor may have unmasked this patient's acquired autoimmune C1-INH deficiency.

Aged↗
PubMed2001

Enhanced T cell apoptosis in common variable immunodeficiency: negative role of the fas/fasligand system and of the Bcl-2 family proteins and possible role of TNF-RS.

CVI is a primary immunodeficiency characterized by a failure of B cell differentiation associated with an array of T cell defects, such as enhanced T cell apoptosis. In this study we investigated the mechanisms underlying CVI enhanced T cell death. We analysed both the expression of Fas using flow cytometry techniques and the expression of FasL mRNA using RT-PCR in CVI T cells. We could not find any significant differences between CVI and normal subjects with regard to Fas expression, although there was a subgroup of CVI patients with very high Fas expression which was accompanied by an up-regulation of FasL mRNA. However, attempts to induce Fas-mediated apoptosis in these high Fas expressing cells, as evaluated by propidium iodide staining and APO2.7 staining, were unsuccessful. We also investigated intracellular levels of Bcl-2, bcl-xl and bax in CD4(+) and CD8(+) CVI T cells, as well as the bax/Bcl-2 ratio, using flow cytometry techniques but could not detect any differences between CVI and normal subjects. Finally we analysed TNF-RI and TNF-RII mRNA expression in CD4(+) and CD8(+) CVI T cells using semiquantitative RT-PCR and found a significant increase in expression of both TNF-Rs in CD4(+) T cells from CVI patients. Our data suggest that the increased expression of both TNF-Rs on T cells may be one of the mechanisms responsible for the accelerated T cell apoptosis in CVI.

Adolescent↗
PubMed2001

Infections in patients with immunodeficiency with thymoma (Good syndrome). Report of 5 cases and review of the literature.

Immunodeficiency with thymoma (Good syndrome, GS) is a rare, adult-onset condition that is characterized by thymoma, hypogammaglobulinemia, and low numbers of peripheral B cells. CD4+ T lymphopenia and an inverted CD4:CD8+ T-cell ratio may be present. Here we report 5 patients with GS and infectious complications who were seen at 3 institutions between 1983 and 1999. Three patients had recurrent sinopulmonary infections, 3 had severe cytomegalovirus (CMV) disease, and 1 had Pneumocystis carinii pneumonia. Review of the literature identified 46 other reports of infections in GS patients. The infections reported in all 51 patients included recurrent sinopulmonary infection (19 cases with documented respiratory pathogens), generally with encapsulated bacteria, most often Haemophilus influenzae (11 cases); CMV disease (5 cases); bacteremia (7 cases); oral or esophageal candidiasis (6 cases); persistent mucocutaneous candidiasis (5 cases); chronic diarrhea (5 cases with documented stool pathogens); urinary tract infections (4 cases); P. carinii pneumonia (3 cases); tuberculosis (2 cases); Kaposi sarcoma (1 case); disseminated varicella (1 case); candidemia (1 case); wound infection with Clostridium perfringens (1 case); Mycoplasma arthritis (1 case); and other infections. Patients with GS present with a spectrum of sinopulmonary infections and pathogens similar to common variable immunodeficiency (CVID). Compared with patients with CVID, opportunistic infections, including severe CMV disease, P. carinii pneumonia, and mucocutaneous candidiasis, appear to be more common in patients with GS, and patients with GS may have a worse prognosis. GS should be ruled out in patients with thymoma or CVID who develop severe, especially opportunistic, infections. Treatment with intravenous immune globulin is recommended for all patients with GS.

Agammaglobulinemia↗
PubMed2000

Characterization of the T cell receptor repertoire in patients with common variable immunodeficiency: oligoclonal expansion of CD8(+) T cells.

Common variable immunodeficiency is characterized by an impairment in antibody production of at least two immunoglobulin isotypes, and abnormalities of both B and T cells have also been described. In this study, a profound alteration of the T cell receptor repertoire was noted, especially in CD8(+) T cells, in CVID patients when compared to a control group. However, the higher number of oligoclonally expanded populations seen in the patient group was not dependent on age, whereas in the control group an age-related accumulation of these populations was noted. Expansion of CD8(+) CD28(-) T cells in these patients is strongly correlated with T cell receptor repertoire restriction. Furthermore, analysis of cytokine production showed a statistically significant increase in IFN-gamma secretion in the patient group. Lastly, CD94 and perforin were expressed at increased frequencies on CD8(+) T cells in the patient group when compared to the control group. We speculate that these findings support the concept that CD8(+) T cells may play an important regulatory role in CVID.

Adult↗
PubMed2000

Mutations in activation-induced cytidine deaminase in patients with hyper IgM syndrome.

Recent studies have shown that mutations in a newly described RNA editing enzyme, activation-induced cytidine deaminase (AID), can cause an autosomal recessive form of hyper IgM syndrome. To determine the relative frequency of mutations in AID, we evaluated a group of 27 patients with hyper IgM syndrome who did not have defects in CD40 ligand and 23 patients with common variable immunodeficiency. Three different mutations in AID were identified in 18 patients with hyper IgM syndrome, including 14 French Canadians, 2 Lumbee Indians, and a brother and sister from Okinawa. No mutations were found in the remaining 32 patients. In the group of patients with hyper IgM syndrome, the patients with mutations in AID were older at the age of diagnosis, were more likely to have positive isohemagglutinins, and were less likely to have anemia, neutropenia, or thrombocytopenia. Lymphoid hyperplasia was seen in patients with hyper IgM syndrome and normal AID as well as the patients with hyper IgM syndrome and defects in AID.

Adolescent↗
PubMed2000

Circulating human B cells that express surrogate light chains and edited receptors.

Immunoglobulin gene recombination can result in the assembly of self-reactive antibodies. Deletion, anergy or receptor editing normally silence B cells that produce these autoantibodies. Receptor editing is highly efficient in mouse B cells that carry pre-recombined autoantibody transgenes or gene "knock-ins". However, it has been difficult to identify cells that have edited receptors in unmanipulated mice and humans. To try to identify such cells we isolated and characterized B cells that coexpress surrogate and conventional light chains (V-preB+L+) from the blood of normal human donors. V-preB+L+ B cells express RAG mRNA, display an unusual heavy and light chain antibody repertoire consistent with antiself reactivity, and show evidence of receptor editing. These cells accumulate in the joints of patients with rheumatoid arthritis, consistent with a role for V-preB+L+ B cells and receptor editing in autoimmune disease.

Agammaglobulinemia↗
PubMed2000

Enhanced apoptosis of T cells in common variable immunodeficiency (CVID): role of defective CD28 co-stimulation.

CVID is a primary immune disorder in which hypogammaglobulinaemia may be associated with a number of T cell defects including lymphopenia, anergy, impaired lymphocyte proliferation and deficient cytokine secretion. In this study we show that T cells of CVID subjects, in comparison with control T cells, undergo spontaneous apoptosis in culture and markedly accelerated apoptosis after gamma-irradiation. Although costimulation of the CD28 receptor following engagement of the TCR/CD3 receptor normally provides a second signal necessary for IL-2 secretion, CD28 costimulation in CVID does not significantly increase IL-2 production, nor does this combination of activators enhance the survival of irradiated CVID T cells, as it does for cultured normal T cells. Addition of IL-2 enhances CVID T cell survival, suggesting that the IL-2 signalling pathways are normal. CVID T cells have similar expression of Bcl-2 to control T cells. CD3 stimulation up-regulates T cell expression of bcl-xL mRNA for normal T cells, but anti-CD28 does not augment bcl-xL expression for CVID subjects with accelerated apoptosis. Defects of the CD28 receptor pathway, leading to cytokine deprivation and dysregulation of bcl-xL, could lead to poor T cell viability and some of the cellular defects observed in CVID.

Adolescent↗
PubMed1999

A multicenter, randomized, double-blind, placebo-controlled trial of high-dose intravenous immunoglobulin for oral corticosteroid-dependent asthma.

To determine the efficacy of high doses of intravenous gammaglobulin (IVIG) for the treatment of severe, steroid-dependent asthma in patients between 6 and 68 years of age, a randomized, double-blind, placebo-controlled multicenter clinical trial was conducted in private and university hospitals in the United States. Patients were randomized to one of three treatment arms: 2 g IVIG/kg/month (16 patients); 1 g IVIG/kg/month (9 patients); or 2 g iv albumin (placebo)/kg/month (15 patients). The treatment consisted of seven monthly infusions followed by a posttreatment observation period. The primary outcome measurement was mean daily prednisone-equivalent dose requirements, determined during the observation month preceding initiation of treatment and compared to the month preceding the seventh infusion. Secondary clinical endpoints measured were pulmonary function, frequency of emergency room visits or hospitalizations, and number of days absent from school or work. When adjusted for body weight, the mean dose requirements fell by 33, 39, and 33% in the placebo, IVIG (1 g/kg), and IVIG (2 g/kg) treatment arms, respectively. The differences between therapies were not statistically different (P = 0.9728). The mean percentage-of-predicted FEV1 fell in all three treatment groups during the treatment period but there was no significant difference between treatment groups (P = 0.8291). There was also no significant difference in the percentage of subjects requiring emergency room visits or hospitalizations or missing days of work/school, among the three treatment groups. The trial was terminated prematurely after interim analysis determined the adverse experience rate was different between the three groups. Three patients, all randomized to the 2-g/kg IVIG dose group, were hospitalized with symptoms consistent with aseptic meningitis. In summary, in this randomized, double-blind, placebo-controlled multicenter study, high doses of IVIG did not demonstrate a clinically or statistically significant advantage over placebo (albumin) infusions for the treatment of corticosteroid-dependent asthma. Subgroup analysis failed to identify markers predicting responsiveness. High-dose IVIG can also be associated with a significant incidence of serious adverse events.

Administration, Oral↗
PubMed1999

Common variable immunodeficiency: clinical and immunological features of 248 patients.

Common variable immunodeficiency (CVI) is a primary immunodeficiency disease characterized by reduced serum immunoglobulins and heterogeneous clinical features. In these studies we describe the clinical and immunological status of 248 consecutively referred CVI patients of age range 3-79 years who have been followed for a period of 1-25 years. The median age at the time of onset of symptoms was 23 years for males and 28 years for females; the mean age at which the diagnosis of CVI was made was 29 years for males and 33 years for females. Forty percent of patients had impaired T cell proliferation to one or more mitogens; lymphocyte transformation to mitogens was directly related to the level of the serum IgG. Females at all ages had higher levels of serum IgM than males. Survival 20 years after diagnosis of CVI was 64% for males and 67% for females, compared to the expected 92% population survival for males and 94% for females. Parameters associated with mortality in this period were lower levels of serum IgG, poorer T cell responses to phytohemagglutinin, and, particularly, a lower percentage of peripheral B cells (P < 0.006).

Adolescent↗
PubMed1999

Sensitization to Aspergillus species in the congenital neutrophil disorders chronic granulomatous disease and hyper-IgE syndrome.

BACKGROUND: Hyper-IgE syndrome (HIE) and chronic granulomatous disease (CGD) are congenital immunodeficiency diseases with increased susceptibility to bacterial and fungal infections. Both carry significant morbidity and mortality rates because of invasive infections by Aspergillus species. We encountered 2 patients, one with HIE and one with CGD, in whom detection of sensitization to Aspergillus species preceded the diagnosis of immunodeficiency. With high-dose systemic corticosteroids for allergic bronchopulmonary aspergillosis (ABPA), an inflammatory disorder caused by sensitization to Aspergillus species, pulmonary abscesses developed in the patient with HIE, and the patient with CGD succumbed to an overwhelming Aspergillus species-induced pneumonia. OBJECTIVE: We sought to assess the prevalence of sensitization to Aspergillus fumigatus and the presence of diagnostic criteria for ABPA in patients with CGD and HIE. METHODS: We measured A fumigatus-specific serum IgE, IgG, and precipitating antibodies as indicators for A fumigatus sensitization in the sera of 18 patients with neutrophil disorders (7 with HIE and 11 with CGD). Hospital records were reviewed for the presence of other diagnostic criteria for ABPA (asthma, elevated total serum IgE concentration, and radiographic abnormalities). RESULTS: Twelve (67%) of 18 patients were sensitized to A fumigatus, as evidenced by precipitating A fumigatus-specific antibodies. Six (33%) of 18 patients had serologic evidence of ABPA. Five of those 6 patients had radiologic abnormalities consistent with a diagnosis of ABPA. One patient with HIE also had asthma, thus fulfilling minimal essential criteria for concurrent ABPA. CONCLUSIONS: Patients with HIE syndrome and CGD have a high incidence of sensitization to Aspergillus species. A clinical picture indistinguishable from ABPA may coexist or emerge in patients with CGD or HIE and create a major management dilemma because systemic corticosteroids may accelerate tissue damage and invasive fungal infections. It is important to distinguish individuals with congenital neutrophil disorders from uncomplicated classic ABPA.

Adult↗
PubMed1999

Treatment of idiopathic CD4 T lymphocytopenia with IL-2.

Idiopathic CD4 T lymphocytopenia (ICL) is an unusual immune defect in which there is an unexplained deficit of CD4 T cells, leading to fungal, parasitic or other serious opportunistic infections. Current treatment efforts are directed at eliminating infections. Here we describe the use of a novel treatment, subcutaneous polyethylene glycol (PEG)-IL-2 injections, in a woman with this disorder, who had chronic severe mycobacterial disease which led to repeated hospitalizations, and advancing respiratory insufficiency. For this patient, PEG-IL-2, 50 000 U/m2, has been given by weekly subcutaneous injections for 5.5 years. This treatment has resulted in marked (and still continuing) long-term immunological improvement with normalized T cell functions and increased CD4 cell numbers. She has had substantial clinical improvement with clearing of mycobacterial disease, reducing hospitalizations and improved lung functions. The improvement seen in this patient suggests that low-dose IL-2 is a safe and practical therapy, which might be useful in other subjects with this potentially serious immune defect.

Aged↗
PubMed1999

B lymphocyte antigen D8/17 and repetitive behaviors in autism.

OBJECTIVE: Monoclonal antibody D8/17 identifies a B lymphocyte antigen with expanded expression in rheumatic fever, Sydenham's chorea, and subgroups of obsessive-compulsive disorder and Tourette's syndrome with repetitive behaviors. The authors examined the rate of D8/17 expression in children with autism and its correlation with severity of repetitive behaviors. METHOD: Blood samples from 18 patients with autism and 14 comparable medically ill children were evaluated for percentage of D8/17-positive B cells by immunofluorescence and for streptococcal antibodies. Severity of repetitive behaviors was also determined. RESULTS: The frequency of individuals with > or =11% D8/17-positive cells was significantly higher in the autistic patients (78%) than the comparison subjects (21%), severity of repetitive behaviors significantly correlated with D8/17 expression, and D8/17-positive patients had significantly higher compulsion scores than D8/17-negative patients. CONCLUSIONS: D8/17 expression is high in patients with autism and may serve as a marker for compulsion severity within autism.

Adolescent↗
PubMed1999

Pneumocystis carinii pneumonia in a 15-year-old with chronic mucocutaneous candidiasis.

A 15-y-old male patient with chronic mucocutaneous candidiasis (CMCC) and new onset adrenal insufficiency developed Pneumocystis carinii pneumonia (PCP). The literature on infectious complications of CMCC is reviewed and clinical and laboratory characteristics of the only previously described case of PCP in CMCC are compared with those of the patient reported here.

Adolescent↗
PubMed1998

IL-10 production in common variable immunodeficiency.

Common variable immunodeficiency, (CVI) is a heterogeneous primary immunodeficiency disease in which there are T and B cell defects. Since IL-10 in conjunction with anti-CD40 promotes secretion of IgG, IgA, and IgM by CVI B cells, these studies were performed to investigate IL-10 production in CVI. Mitogen or anti-CD3 stimulated CVI peripheral blood mononuclear cells, or isolated T cells produced an insignificant amount of IL-10 over background levels. CVI monocyte IL-10 production was substantial and greater than that of normal controls. Anti-IL-10-neutralizing antibody strongly enhanced CVI T cell proliferative responses to PHA, but only to an insignificant extent, soluble antigens. IL-2 plus anti-IL-10 enhanced CVI proliferative responses to antigens significantly more over baseline than for cells of similarly tested normal controls. These data suggest that CVI T cell secretion of IL-10 is deficient, but that monocyte-derived IL-10, plus a relative lack of IL-2 production, could contribute to the defects of cell proliferation in this disorder.

Adolescent↗