Atypical X-linked agammaglobulinemia.
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Agammaglobulinaemia Tyrosine Kinase↗
Biomedical subjects
R A Good
Publications and source records attributed to R A Good.
A potential peptide vaccine against two different strains of influenza virus isolated at intervals of about 10 years.
We have developed a strategy for making synthetic peptide vaccines, in which a peptide, HA127-133, derived from the hemagglutinin (HA) of A/Aichi/2/68(H3N2) influenza virus (Aichi/68) is introduced into the Ab binding component consisting of 43-46 and 54-58 residues of a pigeon cytochrome c analogue peptide, 46F50V54A. Indeed, this hybrid peptide, 46F/HA127-133/54A, induced impressive T-cell responses and antibody production neutralizing infectivity of Aichi/68 in vitro. In a subsequent study we found that 46F/HA127-133/54A(18mer) peptide antigen, which had been prepared by substitution at the central five residues of 46F50V54A with HA127-133, generated T-cell responses and neutralizing antibody responses as well. On the basis of these prior findings, in the present study we analyzed immunopotency of 46F/HA127-133/54A(18mer) in vivo administered in several ways to I-Ab mice. We show herein that this peptide vaccine loaded in multilamellar liposomes without adjuvant protects the mice against infection with Aichi/68 within 2 weeks after final immunization. Further, this peptide vaccine was shown to be effective in preventing infection with a naturally occurring antigenic variant, A/Texas/1/77(H3N2), carrying the same sequence at 127-133 of the HA as Aichi/68 virus. Since this part of the HA is relatively conserved among H3 subtype influenza viruses, our peptide vaccine may become the basis for a new strategy to prepare effective vaccines that will overcome the ineffectiveness of classical vaccines attributable to antigenic drift of influenza viruses.
Animals↗
Genomic organization and structure of Bruton agammaglobulinemia tyrosine kinase: localization of mutations associated with varied clinical presentations and course in X chromosome-linked agammaglobulinemia.
X chromosome-linked agammaglobulinemia is a life-threatening disease that involves a failure in normal development of B lymphocytes and is associated with missense mutations in BTK, a gene encoding a cytoplasmic tyrosine kinase (Bruton agammaglobulinemia tyrosine kinase, EC 2.7.1.112), a member of the Tec family of protein-tyrosine kinases. The genomic organization has been determined by using conventional restriction fragment mapping, extended DNA sequencing, and PCR fragment-sizing approaches. The DNA sequences of the 18 coding exons composing BTK and their flanking-region sequences are reported; an additional exon(s) encodes a 5' untranslated segment. Single-base-pair substitutions and 4-nt deletions resulted in amino acid replacement, premature termination, frameshift, and exon deletion in a group of X chromosome-linked agammaglobulinemia patients exhibiting different clinical presentations and courses. The nature of the mutations is interpreted in terms of the genomic organization of the BTK gene and the disease course in individual patients. Several examples are found in which the same mutation occurs in unrelated patients, and one of these mutations occurs at the same codon that is substituted in the murine form of BTK, resulting in X chromosome-linked immunodeficiency disease. Considerable variation in presentation and disease course in X chromosome-linked agammaglobulinemia appears associated with the nature and position of different missense mutations.
Agammaglobulinaemia Tyrosine Kinase↗
Common major histocompatibility complex class II markers in clinical variants of cicatricial pemphigoid.
Cicatricial pemphigoid (CP) is a chronic autoimmune blistering disease affecting multiple mucous membranes derived from stratified squamous epithelium and occasionally the skin. CP has a wide spectrum of disease manifestations. Patients with oral pemphigoid (OP) have a benign self-limited disease in which pathological changes are restricted to the oral mucosa. On the other hand, patients with ocular cicatricial pemphigoid (OCP), a chronic condition marked with relapses and remissions, have ocular involvement and also perhaps involvement of other mucous membranes. All clinical subsets are characterized by the presence of a similar anti-basement zone autoantibody. The factors that determine the development of one form of CP or the other are not known. In a previous study, we described the association between OCP and the DQB1*0301 allele (P = 0.006). In this study, we have analyzed 22 Caucasian patients with OP and their family members for major histocompatibility complex DRB generic, DQA1, and DQB1 allele associations by PCR-sequence-specific oligonucleotide probe hybridization. The results were compared to those obtained from 17 Caucasian patients with OCP and to control Caucasian alleles and haplotypes. The DQB1*0301 allele frequency was 38.6% in OP, 52.9% in OCP, and 17.8% in controls. Statistically significant associations were detected between the DQB1*0301 allele and both OP (P = 0.0047) and OCP (P < 0.0001). In addition, DRB1*04 showed a statistically significant association (P = 0.005) with OCP when compared to controls. Analysis of major histocompatibility complex class II haplotypes showed significant statistical associations between both OCP and OP and the HLA-DRB1*04, DRB4*0101, DQA1*03, DQB1*0301 haplotype (P < 0.0001 and P = 0.0012, respectively). Our results indicate that DQB1*0301 is a marker of both oral and ocular forms of CP. The analysis of the amino acid sequence of the DQB1 alleles present in both OP and OCP suggested that amino acid residues at position 57 and positions 71-77 may also be markers of CP.
DNA Probes↗
Calorie restriction prevents the occlusive coronary vascular disease of autoimmune (NZW x BXSB)F1 mice.
Male (NZW x BXSB)F1 (W/BF1) mice develop systemic autoimmunity involving autoantibodies, thrombocytopenia, lupus nephritis, and coronary vascular disease (CVD) with myocardial infarction. To determine whether this murine lupus-associated CVD can be prevented by the reduction of dietary calories, male W/BF1 mice were separated into five experimental groups and fed either ad libitum (designated group A, n = 50), fed 32% fewer calories of an otherwise comparable diet (designated group B6, n = 20), or initially fed ad libitum and then switched to reduced calorie intake (RCI) feeding at ages 14, 17, or 22 weeks (designated B14, n = 10; B17, n = 20; or B22, n = 20). Occlusive CVD was prevented by RCI. Life-span was significantly extended among the early onset RCI cohorts, B6 and B14 (P = 0.0001 and P = 0.005), compared to group A mice. Mean anti-cardiolipin autoantibody titers and mean levels of circulating immune complexes were also lowered in RCI mice when all RCI mice were compared to ad libitum fed group A mice. Histological grades of both coronary vascular and glomerular lesions were significantly less than those of group A mice (P < 0.001). Immunoprecipitates indicative of immunoglobulin deposition within coronary or glomerular vascular walls were also substantially less than those of group A mice. These findings indicate a possible causal role for anti-cardiolipin autoantibody in development of autoimmune CVD in W/BF1 mice and suggest that regulating dietary calories can influence the mechanism involved in pathogenesis of autoimmune-associated CVD development.
Animals↗
Successful hematopoietic reconstitution with transplantation of erythrocyte-depleted allogeneic human umbilical cord blood cells in a child with leukemia.
Cord blood, a potent source of hematopoietic stem cells, has been shown to successfully reconstitute hematopoiesis following allogeneic transplantation in a variety of disorders. A major drawback of cord blood has been the risk of transfusion reactions in ABO blood group incompatibility and drastic reduction in the stem cell pool if the cord blood is manipulated to remove red cells prior to cryopreservation or after thawing. This report describes an erythrocyte depletion method employing 3% gelatin-induced erythrocyte sedimentation for the selective removal of red cells from cord blood. The red cell-depleted fraction was shown to be enriched in progenitor cells and in cells secreting hematopoietic cytokines interleukin 3, granulocyte/macrophage colony-stimulating factor, and interleukin 6; a major source for cytokines was from cord T cells. This preparative technique was employed to separate out red cells from cord blood of an infant delivered by cesarean section who had an 8-year-old sibling with leukemia. Histocompatibility testing of cord cells revealed complete matching with the patient. A cord cell transplant of cryopreserved and thawed cells consisting of 4 x 10(7) nucleated cells per kg was administered to the patient following myeloablative chemotherapy. The patient's quick hematologic recovery and 9-month disease-free period to date suggest that 3% gelatin separation of erythrocytes is a simple method that can be successfully used for transplanting cord cells for malignant/nonmalignant diseases.
ABO Blood-Group System↗
The murine c-fgr gene product associated with Ly6C and p70 integral membrane protein is expressed in cells of a monocyte/macrophage lineage.
The c-fgr gene is a member of the Src family of protooncogene tyrosine kinases. A monoclonal antibody (2H2) that recognizes the specific region of the N-terminal domain of the murine c-fgr gene product (Fgr) has been established. With an immune complex kinase assay in a monocytic leukemia cell line, 2H2 monoclonal antibody was shown to precipitate a 59-kDa protein that corresponds in molecular mass to murine Fgr. Fgr was expressed highly in lymph nodes, slightly in spleen and peripheral blood leukocytes, and barely in the thymus and was not detected in bone marrow. In the presence of a mild detergent, Fgr was coimmunoprecipitated with a 70-kDa protein (p70) or with p70 plus several other molecules that were expressed on the cell-surface membrane of macrophage tumor cell lines PU5-1.8 and J774.1, respectively. By contrast, Fgr was not coimmunoprecipitated with a low-affinity receptor for the Fc portion of IgG that is associated with human Fgr. The molecule was also coimmunoprecipitated with the Ly6C molecule from a macrophage cell line (J774.1) that showed protein-tyrosine kinase activity. Peptide mapping revealed that this kinase activity was derived from Fgr. The similarity of relationship between this intramembrane p70 and/or Ly6C and cytoplasmic Fgr to relationships previously reported between T-cell antigen receptor complex, including CD4 and CD8 coreceptors, and Lck or Fyn in T cells and between surface IgM and Lyn or Blk in B cells, suggests that the Fgr and p70 or Ly6C are, indeed, associated with each other and in the murine system may be responsible for recognition of extracellular substances (either cellular or noncellular) and for signal transduction in cells of monocyte/macrophage lineage.
Animals↗
Requirement of donor-derived stromal cells in the bone marrow for successful allogeneic bone marrow transplantation. Complete prevention of recurrence of autoimmune diseases in MRL/MP-Ipr/Ipr mice by transplantation of bone marrow plus bones (stromal cells) from the same donor.
MRL/MP-Ipr/Ipr (MRL/Ipr) mice possess radioresistant (9.5 Gy) abnormal stem cells and show a recurrence of autoimmune diseases within 5 mo of conventional allogeneic bone marrow transplantation. We recently have found that the MHC preference exists between hemopoietic stem cells and stromal cells; when bones are engrafted, donor-derived stromal cells present in the engrafted bones can migrate into the recipient bone marrows, which are replaced with both donor-derived stromal cells and hematopoietic cells. Based on these findings, we attempted to prevent the recurrence of autoimmune diseases in MRL/Ipr mice by the transplantation of both bone marrow cells and bone (as a source of stromal cells). MRL/Ipr mice were irradiated (8.5 Gy) and then reconstituted with C57BL/6 bone marrow cells plus bone grafts. The mice survived more than 48 wk after this treatment. Immunohistologic studies revealed that the mice were completely free from both lymphadenopathy and autoimmune diseases such as lupus nephritis and rheumatoid arthritis. Sera from these mice showed normal levels of circulating immune complexes and rheumatoid factors. Normal functions of both T cells and B cells were noted. Abnormal T cells such as Thy-1+B220+ cells present in nontreated MRL/Ipr mice could not be seen in the thus-treated mice. In addition, to our surprise, spleen cells from treated mice showed completely normal in vitro primary anti-SRBC responses. These results indicate that stromal cells in allogeneic bone marrow transplantation play a crucial role not only in the prevention of graft failure but also in the successful cooperation among APCs, T cells, and B cells. Although MRL/Ipr mice are radiosensitive and usually die of interstitial pneumonia or fatty liver due to the side effects of radiation, it should be noted that this strategy allows a reduction in the radiation dose (9.5 Gy-->8.5 Gy), and that these mice can survive more than 48 wk without showing any symptoms of autoimmune diseases.
Animals↗
Detection of cell specific cluster determinant expression by reverse transcriptase polymerase chain reaction.
We describe a new, rapid, sensitive, and reproducible method for examining gene expression of several cell specific surface cluster determinants, CD2, CD3-gamma, CD4, CD8-beta, CD14, CD19, CD20, CD23, and CD25-alpha, and terminal deoxynucleotidyl transferase which heretofore have been commonly detected by flow cytometry. The method presented uses the reverse transcriptase polymerase chain reaction (RT-PCR) to analyze CD gene expression in stable human cell lines, peripheral blood lymphocytes, bone marrow, and lymph node cells. Polymerase chain reaction products were quantitated by incorporation of radiolabeled nucleotide during PCR and the amount of nucleotide incorporated into DNA was measured by ion exchange filter chromatography. The usefulness of this methodology is demonstrated in an analysis of peripheral blood samples from a patient who presented with B cell deficiency. Results of analyses of peripheral blood samples from this patient by flow cytometry and RT-PCR are similar except that the increased sensitivity of RT-PCR permitted the detection of CD19, CD20, and CD23 in the blood samples of this patient who otherwise appeared to be lacking in all markers of B cell development.
Antigens, CD↗
Determination of amino acids on agretopes of pigeon cytochrome c-related peptides specifically bound to I-A allelic products.
In our prior study it was demonstrated that residues 46 and 54 on a synthetic peptide, AEGFSYTVANKNKGIT (50V), work as an agretope (site contacts with major histocompatibility complex molecules) and residues 50 and 52 function as an epitope (site contacts with T cell receptor), when tri-molecular complexes are formed among 50V,I-Ab and the T cell receptor. 50V was composed of residues 43 to 58 of pigeon cytochrome c (p43-58) except that the aspartic acid (D) at residue 50 was substituted by valine (V). Substitution of agretopic residues on 50V changed this I-Ab-binding peptide to an I-Ak-binding peptide, suggesting that positions 46 and 54 work as an agretope in I-Ak-restricted T cell responses. In the present study we examined whether residues 46 and 54 of 50V worked as agretopes in T cell responses restricted to other I-A haplotypes. The 50V-related peptides with phenylalanine (F) at position 46 and alanine (A) at position 54 bound tightly to I-Ab, I-Ad, I-Aq and I-As molecules and stimulated T cells most potently in mice bearing these I-A haplotypes. In contrast, 50V-related peptides carrying D at position 46 and A at position 54 bound most potently to I-Ak molecules, and the peptides with arginine (R) at position 46 and A at position 54 bound most efficiently to I-Av molecules. The present findings, thus, demonstrate that the agretopic positions on the p43-58 related peptides are preserved in T cell responses restricted to each I-A haplotype studied, and that the specific amino acids on the agretopic positions exist a priori for each I-A allele-specific structure.
Amino Acid Sequence↗
Contribution of host radioresistant T cells to the clonal elimination of minor lymphocyte stimulatory-1a reactive T cells in mouse bone marrow chimeras.
When bone marrow (BM) cells from I-E+ and minor lymphocyte stimulatory (Mls) antigen (Ag) disparate mice (Mls-1b) were transplanted to lethally irradiated Mls-1a mice, Mls-1a reactive T cells were found to be completely deleted from the developing thymocyte population in these [Mls-1b-->Mls-1a] radiation chimeras. It has been shown that BM-derived class II (Ia) positive cells play an essential role in this clonal deletion. Thus, Mls-1a Ag appeared to have been transferred from recipient cells to the Ia+ cells derived from donor BM. These Mls-1a-Ia complexes appear to be responsible for elimination of the Mls-1a reactive T cells that have also been derived from donor BM. However, definition of the cells of the recipient that generate the Mls-1a Ag and transfer them to the BM-derived Ia+ cells has remained unclear to date. In the analysis described herein, we have investigated the tolerogenicity of Mls-1a Ag derived from host T cells which represent a major population of radioresistant cells in the [Mls-1b-->Mls-1a] chimeras. When recipient T cells that had been collected and purified from spleens of [Mls-1b-->Mls-1a] chimeras were administered i.v. into [Mls-1b] chimeras, Mls-1a reactive V beta 6+, V beta 8.1+, or V beta 9+ T cells were completely eliminated. Thus, residual radioresistant host T cells present in the radiation BM chimeras are the cells which produce the Mls-1a Ag. These Mls-1a Ags ultimately contribute to the clonal elimination of Mls-1a reactive T cells from the developing thymocyte population. The present findings indicate that recipient T cells which can survive lethal irradiation and produce intrinsic superantigens alter eventually the T cell repertoire in the thymus which have been developing from precursors of donor BM.
Animals↗
Molecular cloning of feline interleukin 12 p35 reveals the conservation of leucine-zipper motifs present in human and murine IL-12 p35.
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Amino Acid Sequence↗
Analysis of epitopic residues introduced into the hybrid peptide vaccines prepared according to the cassette theory.
In our previous study, we prepared a synthetic peptide vaccine (46F/HA127-133/54A) against influenza strain A/Aichi/2/68 (H3N2) virus by introducing haemagglutinin (HA) 127-133 to an I-Ab,b binding component that consisted of residues 43-46 and 54-58 of an I-Ab,d binding peptide, 46F50V54A. This hybrid peptide vaccine induced considerable immunological responses against A/Aichi/2/68 as well as against the peptide vaccine in I-Ab mice. In the present study, we have attempted to increase the immunogenicity of the peptide vaccine by introducing HA peptides of various lengths into the I-Ab,d binding components consisting of residues 43-46 and 54-58 or 43-47 and 53-58 of 46F50V54A. We demonstrate here that, among the peptide vaccines prepared, 46F/HA127-133/54A (18 mer) consisting of HA127-133 and the I-Ab,d binding component constructed from 43-47 and 53-58 of 46F50V54A induces the most vigorous T-cell responses and neutralizing antibodies against A/Aichi/2/68 in both I-Ab and I-Ad mice.
Amino Acid Sequence↗
Energy restriction prevents and reverses immune thrombocytopenic purpura (ITP) and increases life span of ITP-prone (NZW x BXSB) F1 mice.
Male (NZW x BXSB)F1 (W/BF1) mice develop immune thrombocytopenic purpura (ITP), which involves antiplatelet autoantibodies and shortened platelet life span. To determine whether reduction of dietary energy can prevent the development or reverse the progression of ITP, male W/BF1 mice were separated into five experimental groups and either given free access to semipurified diet (designated Group A, n = 50) or consumed 32% less energy from an otherwise comparable diet (Group B6, n = 20), or were initially allowed free access to diet then switched to energy restriction at ages 14, 17 or 22 wk (Groups B14, n = 10; B17, n = 20; B22, n = 20). Thrombocytopenia was prevented by energy restriction in Group B6 mice. Platelet-associated IgG (PAIgG) autoantibody levels and the number of splenic antiplatelet antibody-forming cells were low (P < 0.01) and the survival of injected IgG-coated RBC was extended in energy-restricted Group B6 mice (P < 0.01) compared with mice in Group A. Group A mice became progressively thrombocytopenic, with platelet counts as low as 34 x 10(10)/L. Progression of thrombocytopenia was reversed when energy restriction was initiated in Groups B14, B17 and B22, with platelet counts > or = 88 x 10(10)/L and reduction of PAIgG. Life span was extended among early onset energy-restricted Group B6 and Group B14 mice (P = 0.0001 and P = 0.005) but not among late onset energy-restricted Group B17 and Group B22 mice (P = 0.06 and P = 0.35) compared with Group A mice.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Comparative analyses of thymocyte and thymic low-density adherent cell functions.
Thymocytes which have developed in the C3H thymus showed depressed proliferative responses to stimulation with anti-CD3 antibody as compared with those which have developed in the thymus of other strains of mice (i.e. AKR). The present study was conducted to analyze immunological functions of the thymic stromal cell population (low-density adherent cells, LDAC) in the C3H mice using allogeneic bone marrow (BM) chimeras established by BM transplantation in the reciprocal combination of AKR and C3H mice as donor or recipient. The thymic LDAC from C3H mice or the [AKR(donor)-->C3H(recipient)] chimeras contained a high proportion of Mac-1+ cells as compared to AKR mice or the [C3H-->AKR] chimeras. The proportion of Mac-1+ cells paralleled the IL-1- and PGE2-secreting ability of the LDAC cultured either in the presence or absence of LPS and also paralleled the antigen-presenting cell functions of the LDAC. Furthermore, after anti-CD3 stimulation the PGE2 inhibited more profoundly proliferative responses of [AKR-->C3H] or normal C3H thymocytes than those of the [C3H-->AKR] chimera or normal AKR thymocytes. A PGE2 inhibitor, indomethacin, reversed the depressed responses of the thymocytes which had developed in the C3H thymus. These findings suggest that the lower responsiveness of thymocytes from [AKR-->C3H] chimeras to anti-CD3 stimulation may be attributable to large amounts of PGE2 secreted by LDAC and/or to increased sensitivity of thymocytes themselves to PGE2.
Animals↗
Bone marrow transplantation therapy using resistant donors for retrovirus-induced leukaemia in mice.
Infection with Rauscher leukaemia virus (RLV) causes erythroleukaemia, anaemia, viraemia, and splenomegaly, features which develop very quickly in mice of strains susceptible to RLV but more slowly or not at all in strains resistant to RLV. We compared the effects of bone marrow transplantation (BMT) of donor cells obtained from a mouse strain resistant to the virus with the effects of BMT of donor cells obtained from strains susceptible to the virus, in recipient virus-susceptible mice which had previously been inoculated with RLV. Our results indicated that bone marrow transplantation from a marrow-resistant donor, but not from a susceptible donor, delayed the expression of leukaemia and delayed death, although such treatment did not appear to inhibit viral infection in susceptible recipients.
Acquired Immunodeficiency Syndrome↗
Induction of immunological tolerance in full major and multiminor histocompatibility-disparate mice using a mixed bone marrow transplantation model.
Bone marrow transplantation (BMT) has been used to induce and maintain immunological tolerance. Such tolerance could facilitate tissue and organ transplantation between the donor and the recipient without need for continuous immune suppression. A protocol employing transplantation of a mixture of T-cell depleted (TCD) syngeneic plus TCD-allogeneic bone marrow cells has been successfully used for induction of transplantation tolerance between mice that differ at components of the major histocompatibility barrier (MHC), or for crossing the xenogenic barrier. We examined the production of specific immunological tolerance using mixed syngeneic plus allogeneic TCD-BMT to cross the entire major plus multiminor histocompatibility barriers. The transplanted mice were repopulated in a stable manner with a mixture of both donor and recipient phenotypes. On histological examination, the mice were reconstituted with hemopoietic and immunocompetent lymphocytes as assayed by their responses to the thymus-dependent cellular antigen, sheep red blood cells (SRBC) in an in vivo plaque-forming cell assay. The transplanted mice were found to be stable chimeras and expressed long lasting tolerance of both donor and recipient cells and yet they were fully reactive to third party cells in mixed lymphocyte culture. These results provide evidence that "supportive" or accessory cells in the syngeneic marrow facilitate maturation of donor marrow cells into fully functioning immunocytes in an allogeneic environment crossing the MHC barrier, which represents the greatest known challenge to allogeneic marrow transplantation in mice. The MHC-mismatched mixed allogeneic transplantation method may improve organ engraftment in human recipients of BMT from a partially mismatched donor or from a cadaver donor, and may significantly improve graft acceptance from a fully matched sibling donor.
Animals↗
[Relation between age of mice and activity and characteristics of serum alkaline phosphatase].
Characteristics of serum alkaline phosphatase (SAP) were investigated in five strains of young and old mice (C57BL/6, BALB/c, C3H/Bi, MRL/Ipr, Ipr, NZB). SAP activity was measured and SAP kinetics was automatically measured by a spectrophotometer. The heat stability and the inhibitor, beta-bromotetramisole, sensitivity of SAP were also determined. Activity of SAP in old mice was significantly lower compared to young mice of the same strain (P < 0.01). SAP of young mice was more heat labile and was more sensitive to inhibitor as compared to SAP of old mice.
Aging↗