Long-term outcome of non-ablative booster BMT in patients with SCID.

SCID is a fatal syndrome caused by mutations in at least 13 different genes. It is characterized by the absence of T cells. Immune reconstitution can be achieved through nonablative related donor BMT. However, the first transplant may not provide sufficient immunity. In these cases, booster transplants may be helpful. A prospective/retrospective study was conducted of 49 SCID patients (28.7% of 171 SCIDs transplanted over 30 years) who had received booster transplants to define the long-term outcome, factors contributing to a need for a booster and factors that predicted success. Of the 49 patients, 31 (63%) are alive for up to 28 years. Age at initial transplantation was found to have a significant effect on outcome (mean of 194 days old for patients currently alive, versus a mean of 273 days old for those now deceased, P=0.0401). Persistent viral infection was present in most deceased booster patients. In several patients, the use of two parents as sequential donors resulted in striking T-and B-cell immune reconstitution. A majority of the patients alive today have normal or adequate T-cell function and are healthy. Nonablative booster BMT can be lifesaving for SCID.

Population prevalence of diagnosed primary immunodeficiency diseases in the United States.

RATIONALE: Although health surveys are routinely used to estimate the population incidence and prevalence of many chronic and acute conditions in the U.S. population, they have infrequently been used for "rare" conditions such as primary immunodeficiency diseases (PID). Accurate prevalence measures are needed to separate the truly rare condition from those that primary care doctors are likely to see in their practices today, if early diagnosis and treatment are to be achieved. METHODS: A national probability sample of 10,000 households was sampled by random digit dialing and screened by telephone to identify how many of the nearly 27,000 household members had been diagnosed with a PID. RESULTS: A total of 23 household members in 18 households were reported with a specific diagnosis for PID (CVID, IgA, IgG, XLA, SCID, CGD), whereas additional cases were reported as a PID without a confirmatory diagnosis. These findings suggest a population prevalence of diagnosed PID in the United States at approximately 1 in 1,200 persons. CONCLUSIONS: Diagnoses of PID in the United States are far more common than suggested in the literature.

The effect of natural killer cell killer Ig-like receptor alloreactivity on the outcome of bone marrow stem cell transplantation for severe combined immunodeficiency (SCID).

Natural killer (NK) cell alloreactions against recipient cells in the setting of bone marrow transplantation have been associated with decreased rates of graft-versus-host disease (GVHD) and improved survival in transplant recipients with myeloid leukemia. These alloreactions are predicted by the absence of recipient HLA class I ligands for donor inhibitory killer Ig-like receptors (KIR). We hypothesized that donor NK cell alloreactions against recipient cells may affect the development of T and B-cell functions and incidence of GVHD in infants with severe combined immunodeficiency (SCID). Of the 156 patients with SCID who had received related bone marrow transplants without pretransplant chemotherapy or posttransplant GVHD prophylaxis, 137 patient-donor pairs were evaluated for the absence of recipient HLA class I ligands for donor inhibitory KIR. Analysis showed that the absence of a KIR ligand had no effect on the incidence or severity of GVHD (RR [corrected] = 0.95, p = 0.84), development of T-cell function (RR [corrected] = 1.05, p = 0.69), production of IgA (p = 0.46) or IgM (p = 0.33), or on 5-year survival (RR [corrected] = 1.21, p = 0.10). Further, in patients possessing native NK cells, the absence of KIR ligands in donors for recipient-inhibitory KIR did not alter transplantation outcomes. This study suggests that inhibitory KIR/HLA interactions do not play a significant role in bone marrow transplantation for SCID.

Pharmacokinetics and tolerability of a new intravenous immunoglobulin preparation, IGIV-C, 10% (Gamunex, 10%).

BACKGROUND AND OBJECTIVES: A new intravenous immunoglobulin (IGIV) process has been developed that integrates efficient inactivation of enveloped virus, using caprylate, with immunoglobulin G (IgG) purification and caprylate removal by column chromatography. Two clinical studies were conducted to compare the pharmacokinetics of the new product, IGIV-C, 10% (Gamunex, 10%), formulated with glycine, with the licensed solvent-detergent (SD)-treated intravenous immunoglobulin IGIV-SD, 10% (Gamimune N, 10%), formulated with glycine, and IGIV-C, 5%, formulated with 10% maltose. MATERIALS AND METHODS: Both studies were randomized, multicentre crossover trials of 18 and 20 (respectively) adult patients with primary humoral immune deficiency in which patients received one IGIV product for three consecutive periods (3-4 weeks) before crossing over to the other product. Pharmacokinetic parameters were determined after the third infusion of each product. RESULTS: IGIV-C, 10% was bioequivalent to IGIV-SD, 10%, with half-lives (t1/2) of 35 and 34 days, respectively. IGIV-C, 5%, was bioequivalent to IGIV-C, 10%, with t1/2 of 35 and 36 days, respectively. The products had comparable safety profiles. CONCLUSIONS: The pharmacokinetic profiles observed in these trials indicate that IGIV-C, 10% may replace, and be administered in a manner similar to, IGIV-SD, 10%.

Unexpected effects of FERM domain mutations on catalytic activity of Jak3: structural implication for Janus kinases.

Janus kinases comprise carboxyterminal kinase, pseudokinase, SH2-like, and N-terminal FERM domains. We identified three patient-derived mutations in the FERM domain of Jak3 and investigated the functional consequences of these mutations. These mutations inhibited receptor binding and also abrogated kinase activity, suggesting interactions between the FERM and kinase domains. In fact, the domains were found to physically associate, and coexpression of the FERM domain enhanced activity of the isolated kinase domain. Conversely, staurosporine, which alters kinase domain structure, disrupted receptor binding, even though the catalytic activity of Jak3 is dispensable for receptor binding. Thus, the Jak FERM domain appears to have two critical functions: receptor interaction and maintenance of kinase integrity.

Cutaneous complications of BCG vaccination in infants with immune disorders: two cases and a review of the literature.

Two infants, one with a T-cell-signaling defect resulting in a primary immunodeficiency syndrome and the other with severe combined immunodeficiency (SCID), are described. Both infants developed cutaneous infections secondary to their bacillus Calmette-Guérin (BCG) vaccinations. Both patients were from countries where BCG is routinely administered in infancy. The infant with the T-cell-signaling defect developed a disseminated infection involving the skin, while the infant with SCID developed a localized cutaneous infection at the site of his BCG immunization. These two cases resemble other reported cases of cutaneous BCG infection following routine vaccination in immunocompromised patients. Mycobacterium bovis infection should be considered in patients with cutaneous eruptions who have received BCG vaccination, especially those who are immunocompromised.

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.

Chronic granulomatous disease. Report on a national registry of 368 patients.

A registry of United States residents with chronic granulomatous disease (CGD) was established in 1993 in order to estimate the minimum incidence of this uncommon primary immunodeficiency disease and characterize its epidemiologic and clinical features. To date, 368 patients have been registered; 259 have the X-linked recessive form of CGD, 81 have 1 of the autosomal recessive forms, and in 28 the mode of inheritance is unknown. The minimum estimate of birth rate is between 1/200,000 and 1/250,000 live births for the period 1980-1989. Pneumonia was the most prevalent infection (79% of patients; Aspergillus most prevalent cause), followed by suppurative adenitis (53% of patients; Staphylococcus most prevalent cause), subcutaneous abscess (42% of patients; Staphylococcus most prevalent cause), liver abscess (27% of patients; Staphylococcus most prevalent cause), osteomyelitis (25% of patients; Serratia most prevalent cause), and sepsis (18% of patients; Salmonella most prevalent cause). Fifteen percent of patients had gastric outlet obstruction, 10% urinary tract obstruction, and 17% colitis/enteritis. Ten percent of X-linked recessive kindreds and 3% of autosomal recessive kindreds had family members with lupus. Eighteen percent of patients either were deceased when registered or died after being registered. The most common causes of death were pneumonia and/or sepsis due to Aspergillus (23 patients) or Burkholderia cepacia (12 patients). Patients with the X-linked recessive form of the disease appear to have a more serious clinical phenotype than patients with the autosomal recessive forms of the disease, based on the fact that they are diagnosed significantly earlier (mean, 3.01 years of age versus 7.81 years of age, respectively), have a significantly higher prevalence of perirectal abscess (17% versus 7%), suppurative adenitis (59% versus 32%), bacteremia/fungemia (21% versus 10%), gastric obstruction (19% versus 5%), and urinary tract obstruction (11% versus 3%), and a higher mortality (21.2% versus 8.6%).

Thymic function after hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency.

BACKGROUND: Immune function can be restored in infants with severe combined immunodeficiency by transplantation of unfractionated bone marrow from HLA-identical donors or T-cell-depleted marrow stem cells from haploidentical donors, with whom there is a single haplotype mismatch, without the need for chemotherapy before transplantation or prophylaxis against graft-versus-host disease. The role of the thymus in this process is unknown. METHODS: We analyzed the phenotypes of circulating T cells and the proliferative responses of peripheral-blood mononuclear cells to phytohemagglutinin in 83 patients with severe combined immunodeficiency who received allogeneic marrow transplants without T-cell ablation from related donors over an 18-year period. We also tested for the presence of episomes of T-cell antigen receptors (extrachromosomal DNA circles formed during intrathymic T-cell development) to assess thymus-dependent T-cell reconstitution. RESULTS: Before and early after transplantation, the numbers of circulating T cells were low, with a predominance of mature CD45RO+ T cells (primarily resulting from the transplacental transfer of maternal cells); T-cell antigen-receptor episomes were undetectable in peripheral-blood mononuclear cells. In 73 of the infants, thymus-derived T cells expressing CD45RA and T-cell antigen-receptor episomes were detected within three to six weeks after transplantation. The mean (+/-SD) value for thymus-dependent T-cell antigen-receptor episomes peaked (at 7311+/-8652 per microgram of peripheral-blood mononuclear-cell DNA) 1 to 2 years after transplantation and declined to low levels (less than 100 episomes per microgram of DNA) within 14 years, as compared with a gradual decline from birth to the age of about 80 years in normal subjects. CONCLUSIONS: The vestigial thymus in infants with severe combined immunodeficiency is functional and can produce enough T cells after bone marrow transplantation to provide normal immune function.

Advances in the understanding and treatment of human severe combined immunodeficiency.

Human severe combined immunodeficiency (SCID) can result from mutations in any one of at least seven different genes, including those for adenosine deaminase, the common cytokine receptor gamma chain, Janus kinase 3, IL-7 receptor alpha chain, recombinase activation genes 1 and 2, and CD45. Except for adenosine deaminase, knowledge concerning the latter causes of human SCID has accrued since 1993. Advances in the treatment of this syndrome have been no less significant. Since 1982 it has been possible, by rigorous depletion of T cells from the donor marrow, to use related marrow donors other than HLA-identical siblings for successful treatment of infants with this condition. The success rate with the latter type of transplant exceeds 95% if a transplant can be performed within the first 3.5 mo of life, making early diagnosis crucial. Recently, gene therapy has also been successful in infants with X-linked SCID.

Transplantation of thymus tissue in complete DiGeorge syndrome.

BACKGROUND: The DiGeorge syndrome is a congenital disorder that affects the heart, parathyroid glands, and thymus. In complete DiGeorge syndrome, patients have severely reduced T-cell function. METHODS: We treated five infants (age, one to four months) with complete DiGeorge syndrome by transplantation of cultured postnatal thymus tissue. Follow-up evaluations included immune phenotyping and proliferative studies of peripheral-blood mononuclear cells plus biopsy of the thymus allograft. Thymic production of new T cells was assessed in peripheral blood by tests for T-cell-receptor recombination excision circles, which are formed from excised DNA during the rearrangement of T-cell-receptor genes. RESULTS: After the transplantation of thymus tissue, T-cell proliferative responses to mitogens developed in four of the five patients. Two of the patients survived with restoration of immune function; three patients died from infection or abnormalities unrelated to transplantation. Biopsies of grafted thymus in the surviving patients showed normal morphologic features and active T-cell production. In three patients, donor T cells could be detected about four weeks after transplantation, although there was no evidence of graft-versus-host disease on biopsy or at autopsy. In one patient, the T-cell development within the graft was demonstrated to accompany the appearance of recently developed T cells in the periphery and coincided with the onset of normal T-cell function. In one patient, there was evidence of thymus function and CD45RA+CD62L+ T cells more than five years after transplantation. CONCLUSIONS: In some infants with profound immunodeficiency and complete DiGeorge syndrome, the transplantation of thymus tissue can restore normal immune function. Early thymus transplantation - before the development of infectious complications - may promote successful immune reconstitution.

Genetic linkage of hyper-IgE syndrome to chromosome 4.

The hyper-IgE syndrome (HIES) is a rare primary immunodeficiency characterized by recurrent skin abscesses, pneumonia, and highly elevated levels of serum IgE. HIES is now recognized as a multisystem disorder, with nonimmunologic abnormalities of the dentition, bones, and connective tissue. HIES can be transmitted as an autosomal dominant trait with variable expressivity. Nineteen kindreds with multiple cases of HIES were scored for clinical and laboratory findings and were genotyped with polymorphic markers in a candidate region on human chromosome 4. Linkage analysis showed a maximum two-point LOD score of 3.61 at recombination fraction of 0 with marker D4S428. Multipoint analysis and simulation testing confirmed that the proximal 4q region contains a disease locus for HIES.

Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency.

BACKGROUND: Since 1968 it has been known that bone marrow transplantation can ameliorate severe combined immunodeficiency, but data on the long-term efficacy of this treatment are limited. We prospectively studied immunologic function in 89 consecutive infants with severe combined immunodeficiency who received hematopoietic stem-cell transplants at Duke University Medical Center between May 1982 and September 1998. METHODS: Serum immunoglobulin levels and lymphocyte phenotypes and function were assessed and genetic analyses performed according to standard methods. Bone marrow was depleted of T cells by agglutination with soybean lectin and by sheep-erythrocyte rosetting before transplantation. RESULTS: Seventy-seven of the infants received T-cell-depleted, HLA-haploidentical parental marrow, and 12 received HLA-identical marrow from a related donor; 3 of the recipients of haploidentical marrow also received placental-blood transplants from unrelated donors. Except for two patients who received placental blood, none of the recipients received chemotherapy before transplantation or prophylaxis against graft-versus-host disease. Of the 89 infants, 72 (81 percent) were still alive 3 months to 16.5 years after transplantation, including all of the 12 who received HLA-identical marrow, 60 of the 77 (78 percent) who were given haploidentical marrow, and 2 of the 3 (67 percent) who received both haploidentical marrow and placental blood. T-cell function became normal within two weeks after transplantation in the patients who received unfractionated HLA-identical marrow but usually not until three to four months after transplantation in those who received T-cell-depleted marrow. At the time of the most recent evaluation, all but 4 of the 72 survivors had normal T-cell function, and all the T cells in their blood were of donor origin. B-cell function remained abnormal in many of the recipients of haploidentical marrow. In 26 children (5 recipients of HLA-identical marrow and 21 recipients of haploidentical marrow) between 2 percent and 100 percent of B cells were of donor origin. Forty-five of the 72 children were receiving intravenous immune globulin. CONCLUSIONS: Transplantation of marrow from a related donor is a life-saving and life-sustaining treatment for patients with any type of severe combined immunodeficiency, even when there is no HLA-identical donor.

Angelman syndrome: are the estimates too low?

More than 300 cases of Angelman Syndrome (AS) have been reported. AS is still considered a clinical diagnosis because only approximately 80% of those individuals who meet the clinical criteria will have a maternal deletion of chromosome 15q11-13. Of the reported cases of AS, very few are of adults with AS. We present our findings on 11 adults with AS identified in a long-term residential care facility for persons with severe developmental disabilities. The diagnosis of AS was not recognized at the time of their admission but was established as part of our evaluation. Thus, there may be an underestimate of the true incidence of AS especially in adults with severe developmental disabilities.

Defective IL7R expression in T(-)B(+)NK(+) severe combined immunodeficiency.

Severe combined immunodeficiency (SCID) is caused by multiple genetic defects. The most common form of SCID, X-linked SCID (XSCID), results from mutations in IL2RG (ref. 4), which encodes the common cytokine receptor gamma chain (gamma(c)) that is shared by the IL-2, IL-4, IL-7, IL-9 and IL-15 receptors. In XSCID and SCID resulting from mutations in JAK3, which encodes a Janus family tyrosine kinase that couples to gamma(c) and is required for gamma(c)-dependent signalling, T- and natural killer (NK)-cells are decreased but B-cell numbers are normal (T(-)B(+)NK(-)SCID). Some SCID patients lack T cells but retain NK cells. Given diminished T-cell development in Il7- or Il7r-deficient mice and that Il/7r-deficient mice have NK cells, we hypothesized that T(-)B(+)NK(+) SCID might result from defective IL-7 signalling, although apparent differences in the role of the IL-7/IL-7R pathway in humans and mice in T-cell and B-cell development have been suggested. We now demonstrate that defective IL7R expression causes T(-)B(+)NK(+) SCID, indicating that the T-cell, but not the NK-cell, defect in XSCID results from inactivation of IL-7Ralpha signalling.

Role of JAK3 in CD40-mediated signaling.

CD40 is a member of the tumor necrosis factor receptor family and plays an important role in B-cell survival, growth, differentiation, and isotype switching. Recently, CD40 has been shown to associate with JAK3, a member of the family of Janus Kinases, which are nonreceptor protein kinases involved in intracellular signaling mediated by cytokines and growth factors. To investigate the role of JAK3 in CD40-mediated signaling, we studied the effect of CD40 stimulation on B-cell proliferation, IgE isotype switching, and upregulation of surface expression of CD23, ICAM-1, CD80, and LT-alpha in JAK3-deficient patients. Our studies show that stimulation of B cells with monoclonal antibody to CD40 in the presence of interleukin-4 (IL-4) or IL-13 resulted in similar responses in JAK3-deficient patients and normal controls. This suggests that JAK3 is not essential for CD40-mediated B-cell proliferation, isotype switching, and upregulation of CD23, ICAM-1, CD80, and LT-alpha surface expression.