Intracellular cytokine production by Th1/Th2 lymphocytes and monocytes of children with symptomatic transient hypogammaglobulinaemia of infancy (THI) and selective IgA deficiency (SIgAD).
(65/604)
Intracellular expression of several cytokines was assessed in lymphocytes and monocytes of children with transient hypogammaglobulinaemia of infancy (THI) and selective IgA deficiency (SIgAD). THI was characterized by an increased frequency of CD3+/CD4+ lymphocytes expressing tumour necrosis factor alpha (TNF-alpha), TNF-beta and interleukin 10 (IL-10), while in SIgAD elevated numbers of these cells containing TNF-alpha and interferon gamma (IFN-gamma) were observed. No changes in the number of CD4+ T cells expressing IL-4 in both diseases were noted. The proportion of CD33+ monocytes containing TNF-alpha both in THI and SIgAD was unchanged. The secretion of IL-12 by peripheral blood mononuclear cells (PBMCs) of patients with THI and SIgAD was significantly elevated and associated with an increased frequency of IL-12 expressing monocytes in THI but not in SIgAD. IL-18 secretion was slightly, but not significantly, elevated in both diseases. Intracellular Th1 and Th2 type cytokines within CD3+/CD4+ lymphocytes were also determined in the normal blood donors that showed high or low production of IgG and IgA in vitro. In low producers of IgG an increased proportion of CD3+/CD4+ cells expressing TNF-alpha and IFN-gamma was found, while in low IgA responders only elevated TNF-alpha positive CD3+/CD4+ cells were observed. These results suggest that THI and SIgAD may represent diseases with an excessive Th1 type response that is associated with an up-regulation of IL-12 secretion and, at least in THI, elevated numbers of monocytes expressing intracellular IL-12. Up-regulation of IL-12 may be the essential factor in the patomechanism(s) of these diseases as already described in common variable immunodeficiency (CVID). (+info)
Pseudomonas aeruginosa septic shock associated with ecthyma gangrenosum in an infant with agammaglobulinemia.
(66/604)
Ecthyma gangrenosum (EG) due to Pseudomonas aeruginosa is a rare and invasive infection that can be associated with agammaglobulinemia. The cornerstone of the treatment is based on prompt recognition with appropriate antibiotic coverage and intravenous immunoglobulin. The authors report a case of EG emphasizing the clinical and therapeutic aspects of this condition. (+info)
Hypogammaglobulinaemia: cumulative experience in 49 patients in a tertiary care institution.
(67/604)
In this paper, clinical data of 49 adult patients with agammaglobulinaemia (syn. hypogammaglobulinaemia), 15 cases of X-linked agammaglobulinaemia (XLA) and 34 of common variable immunodeficiency (CVID) are reviewed. Although immunoglobulin substitution largely abolished life-threatening respiratory tract infections, considerable infectious and non-infectious morbidity was still encountered in these patients. Almost all patients suffered from chronic or recurrent upper and lower airway infections, mainly caused by Haemophilus influenzae and pneumococci. The lower respiratory tract infections led to cumulative damage to the respiratory tract, especially in XLA patients. Also the incidence of infections outside the respiratory tract (giardiasis, Campylobacter jejuni infections) was more common in XLA patients than in CVID patients. Nodular lymphoid hyperplasia was only found in CVID. A variety of other non-infectious complications were seen especially in CVID. Neoplastic complications occurred in nine patients (two cases of thymoma, two colorectal cancer, one gastric carcinoma, two haematological malignancies, two cases of skin cancer). Six patients died (five XLA patients and one CVID patient, from infectious and non-infectious causes). (+info)
A case of severe B cell deficiency after allogeneic stem cell transplantation.
(68/604)
Insufficient immunological reconstitution is one of the serious complications of allogeneic stem cell transplantation (SCT). We report a case of severely impaired B-lymphopoiesis after allogeneic SCT for CML. The patient's bone marrow and blood cells display complete chimerism and he is currently free from leukemia. His serum immunoglobulin levels are below detection level, and B cells are absent at 2 years post transplant in both the bone marrow and blood. Other populations appear to be normal. To the best of our knowledge, this is the first report of B-lymphopoiesis being undetectable more than 2 years after allogeneic SCT. (+info)
Expression of human complement receptor type 2 (CD21) in mice during early B cell development results in a reduction in mature B cells and hypogammaglobulinemia.
(69/604)
Complement receptor (CR) type 2 (CR2/CD21) is normally expressed only during the immature and mature stages of B cell development. In association with CD19, CR2 plays an important role in enhancing mature B cell responses to foreign Ag. We used a murine Vlambda2 promoter/Vlambda2-4 enhancer minigene to develop transgenic mice that initiate expression of human CR2 (hCR2) during the CD43(+)CD25(-) late pro-B cell stage of development. We found peripheral blood B cell numbers reduced by 60% in mice expressing high levels of hCR2 and by 15% in mice with intermediate receptor expression. Splenic B cell populations were altered with an expansion of marginal zone cells, and basal serum IgG levels as well as T-dependent immune responses were also significantly decreased in transgenic mice. Mice expressing the highest levels of hCR2 demonstrated in the bone marrow a slight increase in B220(int)CD43(+)CD25(-) B cells in association with a substantial decrease in immature and mature B cells, indicative of a developmental block in the pro-B cell stage. These data demonstrate that stage-specific expression of CR2 is necessary for normal B cell development, as premature receptor expression substantially alters this process. Alterations in B cell development are most likely due to engagement of pre-B cell receptor-mediated or other regulatory pathways by hCR2 in a CD19- and possibly C3 ligand-dependent manner. (+info)
Clinical and molecular analysis of patients with defects in micro heavy chain gene.
(70/604)
Autosomal recessive disorders of B cell development are rare and heterogeneous. To determine the proportion of affected patients who have defects in the micro heavy chain (IGHM) gene, we used single-stranded conformational polymorphism analysis to screen genomic DNA from 40 unrelated patients with early onset infections, profound hypogammaglobulinemia, and absent B cells. All of the patients were genotypically normal in BTK, the gene that underlies X-linked agammaglobulinemia. Eight different mutations in the micro heavy chain were identified in 19 members of 12 unrelated families. Four of the mutations were large deletions that removed more than 40 kb of DNA in the IGHM locus. In six of the 12 families, the affected patients had an identical single base pair substitution, a G-->A, at the -1 position of the alternative splice site. Immunoglobulin haplotype analysis showed that this mutation occurred on at least three different haplotypes, indicating that this is a hot spot for mutations. Compared with patients with mutations in Btk, patients with defects in the micro heavy chain had an earlier onset of disease and more complications. Our study indicates that at least 20-30% of patients with autosomal recessive defects in B cell development have mutations in the micro heavy chain. (+info)
Complement-mediated clearance of erythrocytes: mechanism and delineation of the regulatory roles of Crry and DAF. Decay-accelerating factor.
(71/604)
The role of complement in the pathogenesis of autoimmune hemolytic anemia (AIHA) has been controversial and may depend on a number of factors, including the affinity and isotype of the pathogenic antibodies involved. We have recently shown that mouse erythrocytes deficient in the membrane C3 regulatory protein, complement receptor 1-related gene/protein y (Crry), but not decay-accelerating factor (DAF), were spontaneously eliminated in vivo by complement. Here, by generating a mouse deficient in both DAF and Crry, we further delineated the roles of Crry and DAF in regulating alternative and classical pathway C3 activation. By using immunoglobulin-, Fcgamma receptor (FcgammaR)-, C3-, C4-, and C5-deficient mice, we also determined the mechanism by which membrane C3 regulator-deficient erythrocytes are cleared from the circulation. Finally, we evaluated the relative importance of the Fc receptor versus the complement pathway in disposing antibody-opsonized DAF/Crry-deficient erythrocytes. We conclude that (1) Crry plays a more dominant role than DAF in regulating the alternative pathway of complement, whereas DAF and Crry are equally effective in preventing antibody-induced runaway complement activation on mouse erythrocytes; (2) DAF/Crry-deficient erythrocytes are eliminated by the alternative pathway of complement via complement receptor-mediated erythrophagocytosis in the spleen; and (3) when opsonized with an immunoglobulin G2a (IgG2a) autoantibody, Crry/DAF-deficient erythrocytes are eliminated more rapidly by complement than by the Fc receptor pathway. These results shed new light on the relative activities of Crry and DAF and underscore the critical roles of membrane C3 regulators in preventing spontaneous and antibody-induced erythrocyte damage in vivo. (+info)
von Recklinghausen disease in a patient with X-linked agammaglobulinemia.
(72/604)
A 33-year-old man was referred to our hospital because of intractable cellulitis in his left lower leg. He was diagnosed with agammaglobulinemia at the age of 6 years and had been receiving gamma-globulin supplementation since then. Laboratory examination revealed a markedly reduced number of B cells, decreased protein amount of Bruton's tyrosine kinase (BTK) in monocytes, and a single base substitution of C994-->T(missense mutation of Arg288-->Trp) in BTK gene, confirming the diagnosis of X-linked agammaglobulinemia (XLA). The patient also had characteristic features of von Recklinghausen disease, such as numerous subcutaneous nodules, cafe-au-lait spots, Lisch nodules in the iris and spinal scoliosis. Biopsy of a subcutaneous nodule confirmed a neurofibroma. Although the influence of XLA on the development of von Recklinghausen disease is unknown for the moment, this is, to our knowledge, the first report of a patient with XLA who also developed von Recklinghausen disease. (+info)