Severe T-cell Immunodeficiency Research Articles

PERIPHERAL BLOOD T-CELL POPULATION (CD4+) IN MEN LIVING IN THE ARCTIC AND IN THE SEMIARID CLIMATIC ZONES

Introduction: Climatic factors are important determinants of human health acting through different mechanisms including the immune system. Long-term exposure to extreme climatic conditions may result in immune response disturbances manifested by secondary immunodeficiency. Aim: To assess the concentration of T-helpers in the peripheral blood (CD4+) of men living in the extreme climatic conditions of the North and the South. Methods: Altogether, 32 men aged from 20 to 60 years from Arkhangelsk (Arctic Russia) and 30 men of the same age from Aleppo (Syria) comprised the sample. The analysis of immune parameters of lymphoid subpopulations of peripheral blood CD3+ (mature lymphoid cells), CD4+ (T-helper cells) was performed by indirect immunoperoxidase reaction using monoclonal antibodies. Results: A deficiency of mature T-lymphocytes (CD3+) was revealed in 93-100 % of the study participants regardless of age and region of residence (0,27-0,62 -109 cells/l). A reduced content of T-helpers (CD4+) was found in 52,9 % and 46,7 % of men in Arkhangelsk at the age of 20-39 and 40-60 years (0,34-0,43 -109 cells/l), respectively. The deficiency of T-helpers in Aleppo men aged 20-39 and 40-60 was found in 40,0 % and 6,7 % of cases. Conclusion: Severe T-cell immunodeficiency was twice as common in young men in the Arctic compared to the residents of semiarid climatic zone of the same age group. Low T-helper activity was 6,7 times more prevalent among the northerners than among the Syrians in the of the older age group.

T–Cell Receptor Excision Circles in HIV–Exposed, Uninfected Newborns Measured During a National Newborn Screening Program for Severe Combined Immunodeficiency

To assess the level of T-cell receptor excision circles (TRECs) in HIV-exposed, uninfected (HEU) infants as well as assess the variables associated with lower TRECs in the study population.Researchers in the study reported on 158 HEU infants born to mothers positive for HIV who were ≥32 weeks’ gestational age between January 2015 and July 2016 from 10 birthing centers in France.The study used the data from 2 separate French national studies from 10 birthing centers. The 2 studies included The French Perinatal Survey of the National Agency for Research on AIDS (EPF Study) (a national epidemiological cohort study of pregnant women positive for HIV and their infants) and the DEPISTREC Study (a national study of TRECs for newborn screening for all infants born in France). TRECs are byproducts made during T-cell development; thus, decreased levels of TRECS suggest a T-cell immunodeficiency. HEU infants were compared with nonexposed, healthy infants from the DEPISTREC Study.The demographics of the 158 infants’ mothers identified (who participated in both the EPF and DEPISTREC studies) were similar to all mothers included in the DEPISTREC Study at the time of analysis. Overall, TREC levels for the HEU infants were lower at 94 copies (range: 54–150) per microliter compared with the TREC levels of the infants not exposed to HIV perinatally (113 copies [range: 76–169] per microliter; P = .001). The study population was separated into 2 groups on the basis of origin ([1] sub-Saharan African or Caribbean decent and [2] other origins) and then individually compared with seronegative mothers in the DEPISTREC cohort. The 126 infants with sub-Saharan African or Caribbean decent had significantly lower TREC levels than the infants with seronegative mothers, whereas the 32 infants of other origin had no significant difference in TREC levels when compared with the infants with seronegative mothers.Researchers in the study concluded that when controlling for gestational age, overall, the HEU newborns had a lower TREC level than unexposed infants. They were unable to determine if control of maternal HIV viral replication had any effect on HEU infant TREC level. This study also noted that infants with sub-Saharan African or Caribbean decent had a significantly lower TREC level when compared with both HEU infants of other origin and the infants with seronegative mothers in the DEPISTREC study. Importantly, a previous study completed on New York State severe combined immunodeficiency disease and T-cell immunodeficiency newborn screening showed that infants of African American decent had lower TREC levels than infants of other origins in the general population.This study used the newborn screening program for severe combined immunodeficiency disease and T-cell immunodeficiency to assess the level of TRECs in HEU infants. When the study cohort was separated on the basis of origin, HEU infants of sub-Saharan African or Caribbean decent had a significantly lower TREC level than HEU infants of other origins. This suggests that patients with African descent may have lower TREC levels, in general, irrespective of HEU status.

Concise Review: Boosting T-Cell Reconstitution Following Allogeneic Transplantation-Current Concepts and Future Perspectives.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice for a large number of malignant and nonmalignant (inherited) diseases of the hematopoietic system. Nevertheless, non‐HLA identical transplantations are complicated by a severe T‐cell immunodeficiency associated with a high rate of infection, relapse and graft‐versus‐host disease. Initial recovery of T‐cell immunity following HSCT relies on peripheral expansion of memory T cells mostly driven by cytokines. The reconstitution of a diverse, self‐tolerant, and naive T‐cell repertoire, however, may take up to 2 years and crucially relies on the interaction of T‐cell progenitors with the host thymic epithelium, which may be altered by GvHD, age or transplant‐related toxicities. In this review, we summarize current concepts to stimulate reconstitution of a peripheral and polyclonal T‐cell compartment following allogeneic transplantation such as graft manipulation (i.e., T‐cell depletion), transfusion of ex vivo manipulated donor T cells or the exogenous administration of cytokines and growth factors to stimulate host‐thymopoiesis with emphasis on approaches which have led to clinical trials. Particular attention will be given to the development of cellular therapies such as the ex vivo generation of T‐cell precursors to fasten generation of a polyclonal and functional host‐derived T‐cell repertoire. Having been tested so far only in preclinical mouse models, clinical studies are now on the way to validate the efficacy of such T‐cell progenitors in enhancing immune reconstitution following HSCT in various clinical settings. stem cells translational medicine 2019;00:1–8

Severe Epstein–Barr virus infection in primary immunodeficiency and the normal host

Epstein-Barr virus (EBV) infection is ubiquitous in humans, but the majority of infections have an asymptomatic or self-limiting clinical course. Rarely, individuals may develop a pathological EBV infection with a variety of life threatening complications (including haemophagocytosis and malignancy) and others develop asymptomatic chronic EBV viraemia. Although an impaired ability to control EBV infection has long been recognised as a hallmark of severe T-cell immunodeficiency, the advent of next generation sequencing has identified a series of Primary Immunodeficiencies in which EBV-related pathology is the dominant feature. Chronic active EBV infection is defined as chronic EBV viraemia associated with systemic lymphoproliferative disease, in the absence of immunodeficiency. Descriptions of larger cohorts of patients with chronic active EBV in recent years have significantly advanced our understanding of this clinical syndrome. In this review we summarise the current understanding of the pathophysiology and natural history of these diseases and clinical syndromes, and discuss approaches to the investigation and treatment of severe or atypical EBV infection.

Epidemiology of Fusariosis

Fusarium spp. are molds widely distributed in nature as soil saprophytes. Human infections by Fusarium spp. occur both in immunocompetent and immunocompromised hosts. The most common forms in immunocompetent individuals are onychomycosis and keratitis. By contrast, disseminated fusariosis affects the immunocompromised host, especially hematopoietic cell transplant recipients and patients with acute leukemia. Severe neutropenia and T-cell immunodeficiency are the most important predisposing factors. Infection in compromised hosts is frequently fatal, and successful outcome is largely determined by the degree and persistence of immunosuppression and the extent of infection. The frequency of invasive fusariosis is increasing in some regions, especially in South America.

Foetal presentation of cartilage hair hypoplasia with extensive granulomatous inflammation

Cartilage-hair-hypoplasia is a rare autosomal recessive metaphyseal dysplasia due to RMRP (the RNA component of the RNase MRP ribonuclease mitochondrial RNA processing complex) gene mutations. So far, about 100 mutations have been reported in the promoter and the transcribed regions. Clinical characteristics include short-limbed short stature, sparse hair and defective cell-mediated immunity. We report herein the antenatal presentation of a female foetus, in whom CHH was suspected from 23 weeks' gestation, leading to a medical termination of the pregnancy at 34 weeks gestation, and thereafter confirmed by morphological and molecular studies. Post-mortem examination confirmed short stature and limbs, and revealed thymic hypoplasia associated with severe CD4 T-cell immunodeficiency along with extensive non caseating epithelioid granulomas in almost all organs, which to our knowledge has been described only in five cases. Molecular studies evidenced on one allele the most frequently reported founder mutation NR_003051: g.70A>G, which is present in 92% of Finnish patients with Cartilage Hair Hypoplasia. On the second allele, a novel mutation consisting of a 10 nucleotide insertion at position −18 of the promoter region of the RMRP gene (M29916.1:g.726_727insCTCACTACTC) was detected. The founder mutation was inherited from the father, and the novel mutation from the mother. To our knowledge, this case report represents the first detailed foetal analysis described in the literature.

Tetralogy of Fallot with Complete DiGeorge Syndrome: Report of a Case and a Review of the Literature

Complete DiGeorge syndrome (CDGS) has a severe T-cell immunodeficiency and is fatal without thymus or bone marrow transplantation. Associated congenital heart disease (CHD) further complicates the clinical management. We report an infant with tetralogy of Fallot, confluent and hypoplastic pulmonary arteries, right aortic arch, and aberrant left subclavian artery. He was athymic with no CD3+ T cells. CDGS was diagnosed with 22q11.2 deletion. The patient underwent central aortopulmonary shunt at 12 days of age. The patient died at 5 weeks of age awaiting thymus transplantation. We performed a review of the literature regarding CDGS and CHD. We found 43 cases including conotruncal defects (20) and nonconotruncal defects (23). The overall mortality rate was 67%. Among 30 cases undergoing transplantation (bone marrow 16 and thymus 12, bone marrow + thymus 2), the mortality rate was 53%. The patients with conotruncal defects were more likely to die before transplantation (45% vs. 16%, P =.04). The main cause of death was infection before and after transplantation. We conclude that children with CDGS and CHD have a high mortality. Bone marrow and thymus transplantation can improve the survival, but the overall management of these high risk patients remains challenging.

Disseminated fusariosis in immunocompromised patients

Immunocompromised patients are at high risk of developing serious disseminated infections by opportunistic fungi (Aspergillus, Candida, and Fusarium spp), which frequently present as cutaneous lesions, sometimes as a first sign. Prolonged and deep neutropenia, immunodepressive treatments (systemic steroids and chemotherapy) and severe T-cell immunodeficiency are the most important risk factors. We report 2 patients with acute lymphoblastic leukemia, who developed multiple tender erythematous skin lesions on their legs and arms during chemotherapy treatment. Skin biopsies for histology and culture studies established the diagnosis of Fusarium infection. They received treatment with systemic antifungal and granulocyte colony-stimulting factor. The infection responded after recovering from neutropenia. Early diagnosis and treatment is very important to improve the prognosis, because these infections in immunodepressed hosts have a high mortality rate.

CMV central nervous system disease in stem-cell transplant recipients: an increasing complication of drug-resistant CMV infection and protracted immunodeficiency

We report on two patients with no active GVHD and on moderate doses of immunosuppressive drugs who unexpectedly developed fatal CMV meningoencephalitis after umbilical cord blood transplantation. A review of these two cases along with nine other cases of CMV central nervous system (CNS) disease after allogeneic SCT that were mostly reported within the last 8 years suggests that this severe complication of CMV infection may be increasing. CMV CNS disease after allogeneic SCT is a late-onset disease (median time of onset, 210 days) and is usually manifested as encephalitis in the absence of other sites of CMV disease. The development of CMV CNS disease is associated with risk factors (T-cell depletion, anti-thymocyte globulin, umbilical cord blood transplantation) that cause severe and protracted T-cell immunodeficiency (8 of 11 cases), a history of recurrent CMV viremia treated with multiple courses of preemptive ganciclovir or foscarnet therapy (11 of 11 cases), and ganciclovir-resistant CMV infection (11 of 11 cases). Despite therapy with a combination of antiviral drugs (ganciclovir, foscarnet and cidofovir), mortality is high (10 of 11 cases). Given this high mortality, extended prophylaxis with current or novel antiviral drugs and strategies to enhance CMV immunity need to be considered in high-risk patients.

Hepatitis and Human Bocavirus Primary Infection in a Child with T-Cell Deficiency

Human bocavirus (HBoV) is one of the recently identified respiratory viruses. The clinical features of HBoV infection have not yet been fully elucidated. We report an invasive HBoV infection and hepatitis in a boy with cartilage-hair hypoplasia and severe T-cell immunodeficiency.

Lack of Nonfunctional B-cell Receptor Rearrangements in a Patient with Normal B Cell Numbers Despite Partial RAG1 Deficiency and Atypical SCID/Omenn Syndrome

A 2.5-month old boy presented with recurrent wheezing, protracted diarrhea, erythrodermia, and failure to thrive. Laboratory analysis showed lymphocytopenia with severely reduced T-cell numbers but normal numbers of B and NK cells. Serum IgE was increased and the patient had eosinophilia. These presentations are consistent with atypical severe combined immunodeficiency (SCID)/Omenn Syndrome and the diagnosis was confirmed by demonstration of homozygosity for the R841W mutation in the catalytic core of RAG1. Comparison of the patient's immunoglobulin heavy chain rearrangements to those of age-matched controls, cord blood, and adults revealed an almost total lack of nonproductive rearrangements (2.7% versus 14.7%, 27.6%, and 19.8% in the controls, respectively) indicating failure to correct out-of-frame rearrangements by a second rearrangement on the homologous chromosome 14. We hypothesize that the R841W mutation causes a malfunction of RAG1 that has differential outcome on V(D)J recombination in B and T cells, as the patient had normal B cell numbers but suffered severe alpha-beta T-cell immunodeficiency.

Long-term immune reconstitution and clinical outcome after stem cell transplantation for severe T-cell immunodeficiency

Currently, hematopoietic stem cell transplantation allows long-term survival in a high proportion of infants with congenital severe T-cell immunodeficiency. However, relatively little is known of their long-term quality of life. We sought to assess the long-term immune reconstitution and clinical status in children treated with stem cell transplantation for severe T-cell immunodeficiency. Immune function and clinical status have been analyzed in a cohort of 40 patients with severe T-cell immunodeficiency who are alive at a follow-up of at least 5 years after transplantation. Most patients have attained normal T- and B-cell function. Weight and height were normal at last follow-up in most patients. Endocrine and severe neurologic abnormalities have been observed in 17.5% and 10% of the patients, respectively. These data indicate that with current management strategies, stem cell transplantation can lead to long-term survival and good quality of life in the majority of patients with severe T-cell immunodeficiency. Prompt recognition of congenital severe T-cell immunodeficiency, followed by stem cell transplantation, allows excellent perspectives of long-term survival and good quality of life for these otherwise fatal disorders.

Immunodeficiency and Autoimmunity in 22q11.2 Deletion Syndrome

22q11.2 deletion syndrome is the commonest chromosome deletion syndrome. 22q11.2 deletion may result in variable clinical phenotypes which may differ even between patients with identical deletions. Abnormal pharyngeal arch development results in defects in the development of the parathyroid glands, thymus and conotruncal region of the heart. Defective thymic development is associated with impaired immune function. 'Complete' DiGeorge syndrome with total absence of the thymus and a severe T-cell immunodeficiency accounts for <0.5% of patients. The majority of patients with 22q11.2 deletion syndromes have 'partial' defects with impaired thymic development rather than complete absence with variable defects in T-cell numbers. Immunodeficiency in these patients is not solely due to T-cell deficiency and abnormalities of T-cell clonality or impairment of proliferative responses may play a role. Humoral deficiencies including defects in the B-cell compartment have also been identified in these patients. 22q11.2 deletion syndrome patients are at increased risk of a variety of autoimmune diseases. A number of immune defects may predispose to the development of autoimmunity in these patients including increased infection, impaired development of natural T-regulatory cells and impaired thymic central tolerance.

Successful Allogeneic Hemopoietic Stem Cell Transplantation in a Child Who Had Anhidrotic Ectodermal Dysplasia With Immunodeficiency

Anhidrotic ectodermal dysplasia with immunodeficiency is associated with multiple infections and a poor clinical outcome. Hypomorphic mutations in nuclear factor kappaB essential modulator (NEMO)/IkappaB kinase complex and a hypermorphic mutation in inhibitor alpha of nuclear factor kappaB (IkappaBalpha) both result in impaired nuclear factor kappaB activation and are associated with X-recessive and autosomal-dominant forms of anhidrotic ectodermal dysplasia with immunodeficiency, respectively. Autosomal-dominant anhidrotic ectodermal dysplasia with immunodeficiency is also associated with a severe T-cell phenotype. It is not known whether hematopoietic stem cell transplantation can cure immune deficiency in children with anhidrotic ectodermal dysplasia with immunodeficiency. A boy with autosomal-dominant anhidrotic ectodermal dysplasia with immunodeficiency and a severe T-cell immunodeficiency underwent transplantation at 1 year of age with haploidentical T-cell-depleted bone marrow after myeloablative conditioning. Engraftment occurred, with full hematopoietic chimerism. Seven years after transplantation, clinical outcome is favorable, with normal T-cell development. As expected, the developmental features of the anhidrotic ectodermal dysplasia syndrome have appeared and persisted. This is the first report of successful hematopoietic stem cell transplantation in a child with anhidrotic ectodermal dysplasia with immunodeficiency. Hematopoietic stem cell transplantation is well tolerated and efficiently cures the profound immunodeficiency associated with autosomal-dominant anhidrotic ectodermal dysplasia with immunodeficiency.

Umbilical Cord Blood Stem Cell Transplantation in Severe T-Cell Immunodeficiency Disorders

Hematopoietic stem cell transplantation is the treatment of choice for severe primary T-cell immunodeficiencies. When an HLA-identical sibling as the donor is not available, an alternative donor stem cell source is needed. In primary T-cell immunodeficiencies, T-cell–depleted HLA-haploidentical bone marrow transplantation has been particularly successful in reconstituting the immune system in many but not all of the severe T-cell immune deficiency disorders. This study reports the use of umbilical cord blood (UCB) stem cell transplantation in 16 patients with severe T cell immune deficiency disorders. UCB was evaluated as a stem cell source for immune reconstitution in children with severe primary T-cell immunodeficiency disorders, such as severe combined immunodeficiency syndrome (SCID), reticular dysgenesis, thymic dysplasia, combined immunodeficiency disease (CID), and Wiskott-Aldrich syndrome (WAS) when an HLA-matched sibling donor was unavailable. From 1996 through 2004, 16 children diagnosed with se...

Treatment of B-lymphoproliferative disorder with a monoclonal anti–interleukin-6 antibody in 12 patients: a multicenter phase 1-2 clinical trial

Severe T-cell immunodeficiency after solid organ or bone marrow transplantation may result in the uncontrolled outgrowth of latently Epstein-Barr virus-infected B cells, leading to B-lymphoproliferative disorder (BLPD). Given the potentially important pathogenic role of IL-6 in BLPD, it was tested whether the in vivo neutralization of IL-6 by a monoclonal anti-IL-6 antibody could contribute to the control of BLPD. Safety and efficacy were assessed in 12 recipients of transplanted organs who had BLPD refractory to the reduction of immunosuppression over 8 days. Five patients received 0.4 mg/kg per day. The next 7 patients received 0.8 mg/kg per day. Treatment was scheduled to last 15 days. It was completed in 10 patients, and in the other 2 patients was discontinued early (days 10 and 13, respectively) because of disease progression. Treatment tolerance was good, and no major side effects were observed. High C-reactive protein levels were found in 9 patients before treatment but were normalized under treatment in all patients, demonstrating efficient IL-6 neutralization. Complete remission (CR) was observed in 5 patients and partial remission (PR) in 3 patients. Relapse was observed in 1 of these 8 patients in whom remission was observed. This relapse was unresponsive to treatment. Disease was stable in 1 patient, but it progressed in 3 patients. Seven patients are alive and well. Two patients died because of disease progression, and 3 patients died while in CR (chronic rejection in 2 patients and BLPD sequelae in 1 patient). These data suggest that the anti-IL-6 antibody is safe and should be further explored in the treatment of BLPD.

Immucillin‐H binding to purine nucleoside phosphorylase reduces dynamic solvent exchange

The rate and extent of hydrogen/deuterium (H/D) exchange into purine nucleoside phosphorylase (PNP) was monitored by electrospray ionization mass spectrometry (ESI-MS) to probe protein conformational and dynamic changes induced by a substrate analogue, products, and a transition state analogue. The genetic deficiency of PNP in humans is associated with severe T-cell immunodeficiency, while B-cell immunity remains functional. Inhibitors of PNP have been proposed for treatment of T-cell leukemia, to suppress the graft-vs.-host response, or to counter type IV autoimmune diseases without destroying humoral immunity. Calf spleen PNP is a homotrimer of polypeptide chains with 284 amino residues, molecular weight 31,541. Immucillin-H inhibits PNP with a Kd of 23 pM when only one of the three catalytic sites is occupied. Deuterium exchange occurs at 167 slow-exchange sites in 2 h when no catalytic site ligands are present. The substrate analogue and product prevented H/D exchange at 10 of the sites. Immucillin-H protected 32 protons from exchange at full saturation. When one of the three subunits of the homotrimer is filled with immucillin-H, and 27 protons are protected from exchange in all three subunits. Deuterium incorporation in peptides from residues 132-152 decreased in all complexes of PNP. The rate and/or extent of deuterium incorporation in peptides from residues 29-49, 50-70, 81-98, and 112-124 decreased only in the complex with the transition state analogue. The peptide-specific H/D exchange demonstrates that (1) the enzyme is most compact in the complex with immucillin-H, and (2) filling a single catalytic site of the trimer reduces H/D exchange in the same peptides in adjacent subunits. The peptides most highly influenced by the inhibitor surround the catalytic site, providing evidence for reduced protein dynamic motion caused by the transition state analogue.

Kinetics of T-cell development of umbilical cord blood transplantation in severe T-cell immunodeficiency disorders

Background: Hematopoietic stem-cell transplantation is the treatment of choice for severe primary T-cell immunodeficiencies. When an HLA-identical sibling donor is not available, an alternative donor stem-cell source is needed. In primary T-cell immunodeficiencies, T-cell–depleted HLA-haploidentical bone marrow transplantation has been particularly successful in reconstituting the T-cell immune system in many of the severe combined immunodeficiency syndrome types. However, there are some problems associated with this preparation as a stem donor source, such as increased resistance to engraftment, a long period of time for T-cell engraftment to occur, and failure to engraft B cells and B-cell functions. These problems can be especially troublesome if the patient is infected before the transplantation. Objective: Umbilical cord blood was evaluated as a stem-cell source for immune reconstitution in children with severe primary T-cell immunodeficiency disorders, such as severe combined immunodeficiency syndrome, reticular dysgenesis, thymic dysplasia, and combined immunodeficiency disease, when a matched sibling donor was unavailable. Methods: From January 1996 through July 1997, 6 children received unrelated cord blood stem-cell transplantation after a preparative regimen for the treatment of combined immunodeficiency diseases. The patients ranged in age from 2 weeks to 6 years. The cord blood units were 3 of 6 HLA antigen matches in 2 children, 4 of 6 HLA antigen matches in 3 children, and 5 of 6 HLA antigen matches in 1 child, with molecular HLA-DR mismatch in 3 of the children. Results: The average time for neutrophil engraftment (absolute neutrophil count, >500/mm 3) was 12 days (range, 10 to 15 days), and the average time for platelet engraftment (platelet count, >20,000/mm 3) was 36 days (range, 24 to 50 days). In a patient with reticular dysgenesis, the first transplant failed to engraft but fully engrafted after a second unrelated donor cord blood transplantation. Five of 6 patients exhibited grade I graft-versus-host disease (GvHD), although 1 child experienced grade IV skin and gut GvHD. Immunologic reconstitution demonstrated that cord blood stem-cell transplantation resulted in consistent and stable T-cell, B-cell, and natural killer–cell development. The kinetics of recovery of phenotypic expression and function of T cells occurred between 60 to 100 days and that of natural killer cells at approximately 180 days. B cells engrafted early, and a study of functional B-cell antibody responses revealed that 2 of 2 patients in whom intravenous immune globulin was discontinued have low detectable antibody responses to tetanus and diphtheria toxoid immunizations more than 1 year after the transplantation. Conclusions: Unrelated umbilical donor cord blood is an excellent source of stem cells for transplantation of children with immune deficiency disorders. Benefits include rapid and reliable recovery of immune function, low risk of GvHD, and low viral transmission rate. (J Allergy Clin Immunol 1999;103:823-32.)

Diffuse Large-cell Lymphoma of B-cell Origin and Deficient T-cell Function in a Patient With Rheumatoid Arthritis

An increased incidence of non-Hodgkin's lymphoma has been described in patients with rheumatoid arthritis. Mechanisms related to abnormal immune regulation have been postulated, but no patients with rheumatoid arthritis and lymphoma have been previously well characterized immunologically. We describe here a patient with long-standing rheumatoid arthritis in whom a B-cell diffuse large-cell lymphoma developed. He was found to have a severe T-cell immunodeficiency and evidence of persistent Epstein-Barr virus infection. Epstein-Barr nuclear antigen was not found to be present within lymphoma cells. The combination of defective T-cell function and persistent Epstein-Barr virus infection may have predisposed this patient with rheumatoid arthritis to the development of a malignant clone of B lymphocytes.

Deoxycytidine therapy in two patients with adenosine deaminase deficiency and severe immunodeficiency disease

Two children with adenosine deaminase (ADA) deficiency and combined immunodeficiency disease were given parenteral deoxycytidine in order to reverse the severe T-cell immunodeficiency associated with this disease. One patient received a total of three courses of parenteral deoxycytidine. On two occasions deoxycytidine (50 mg/kg/day) was infused intravenously continuously for 2 weeks. During one of the infusions she received the deoxycytidine deaminase inhibitor tetrahydrouridine (THU). Steadystate levels of plasma deoxycytidine increased 4-fold with THU. RBC dCTP dATP increased more than 10-fold after 48 hr of deoxycytidine infusion. Immunologic studies following the intravenous infusion of deoxycytidine showed transient improvement in T-cell immunity. The third course of deoxycytidine (50 mg/kg/day) was administered subcutaneously during a 10-hr night-time infusion. After 6 and 12 weeks of nightly subcutaneous infusions, there was minimal improvement in the in vitro immunologic studies and no clinical improvement. The second patient received a single 2-week course of continuous intravenous deoxycytidine (50 mg/kg/day) following which there was no significant change in T-cell immunity. This study defines some of the pharmacologic parameters of human deoxycytidine metabolism and suggests that some patients with ADA deficiency may respond to deoxycytidine therapy with improvement in T-cell-mediated immunity, although the changes are small and the effect on clinical status appears to be limited.