RESUMO
To identify genetic effects modulating the blood stage replication of the malarial parasite, we phenotyped a group of 25 inbred mouse strains for susceptibility to Plasmodium chabaudi chabaudi AS infection (peak parasitemia, survival). A broad spectrum of responses was observed, with strains such as C57BL/6J being the most resistant (low parasitemia, 100% survival) and strains such as NZW/LacJ and C3HeB/FeJ being extremely susceptible (very high parasitemia and uniform lethality). A number of strains showed intermediate phenotypes and gender-specific effects, suggestive of rich genetic diversity in response to malaria in inbred strains. An F2 progeny was generated from SM/J (susceptible) and C57BL/6J (resistant) parental strains, and was phenotyped for susceptibility to P. chabaudi chabaudi AS. A whole-genome scan in these animals identified the Char1 locus (LOD=7.40) on chromosome 9 as a key regulator of parasite density and pointed to a conserved 0.4-Mb haplotype at Char1 that segregates with susceptibility/resistance to infection. In addition, a second locus was detected in [SM/J × C57BL/6J] F2 mice on the X chromosome (LOD=4.26), which was given the temporary designation Char11. These studies identify a conserved role of Char1 in regulating response to malaria in inbred mouse strains, and provide a prioritized 0.4-Mb interval for the search of positional candidates.
Assuntos
Predisposição Genética para Doença , Malária/genética , Plasmodium chabaudi , Animais , Modelos Animais de Doenças , Feminino , Haplótipos , Masculino , Camundongos , Camundongos Endogâmicos , FenótipoRESUMO
Cerebral malaria (CM) is an acute, generally lethal condition characterized by high fever, seizures and coma. The genetic component to CM can be investigated in mouse models that vary in degree of susceptibility to infection with Plasmodium berghei ANKA. Using survival time to measure susceptibility in an informative F2 cross (n=257), we identified linkage to chromosome 19 (Berr5 (Berghei resistance locus 5), LOD=4.69) controlling, in part, the differential response between resistant BALB/c and susceptible C57BL/6 progenitors. BALB/c alleles convey increased survival through the cerebral phase of infection but have no quantitative effect on parasitemia during the later, anemic phase. The Berr5 locus colocalizes with three other immune loci, including Trl-4 (tuberculosis resistance), Tsiq2 (T-cell secretion of IL-4) and Eae19 (experimental allergic encephalitis 19), suggesting the possibility of a common genetic effect underlying these phenotypes. Potential positional candidates include the family of Ifit1-3 (interferon-inducible protein with tetratricopeptide repeats 1-3) and Fas.
Assuntos
Mapeamento Cromossômico , Predisposição Genética para Doença , Malária Cerebral/genética , Plasmodium berghei/isolamento & purificação , Alelos , Animais , Escore Lod , Malária Cerebral/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Locos de Características QuantitativasRESUMO
Resistance to blood-stage malaria in AcB55 and AcB61 is caused by a loss of function mutation in pyruvate kinase (Pklr(I90N)). Likewise, pyruvate kinase (PK) deficiency in humans is protective against Plasmodium replication in vitro. We identified a third AcB strain, AcB62 that also carries the Pklr(I90N) mutation. However, AcB62 mice were susceptible to P.chabaudi infection and showed high levels of parasite replication (54-62% peak parasitemia). AcB62 mice showed the hallmarks of PK deficiency-associated anemia similar to AcB55/61 with reticulocytosis, splenic red pulp expansion, tissue iron overload, and increased expression of iron metabolism proteins. This suggests that malaria susceptibility in AcB62 is not because of absence of PK deficiency-associated pathophysiology. To map novel genetic factors affecting malaria susceptibility in AcB62, we generated an informative F2 population using AcB62 (Pklr(I90N)) and CBA-Pk(slc) (Pklr(G338D)) as progenitors and identified a novel locus on chromosome 9 (Char10; LOD=7.24) that controls peak parasitemia. A weaker linkage to the Pklr region of chromosome 3 (LOD=3.7) was also detected, a finding that may reflect the segregation of the two defective Pklr alleles. AcB62 alleles at both loci are associated with higher peak parasitemia. These results identify Char10 as a novel locus modulating severity of malaria in the context of PK deficiency.
Assuntos
Cromossomos Humanos Par 9/genética , Suscetibilidade a Doenças/imunologia , Malária/genética , Piruvato Quinase/deficiência , Alelos , Anemia Hemolítica Congênita/genética , Anemia Hemolítica Congênita/imunologia , Animais , Estruturas Cromossômicas/genética , Humanos , Malária/imunologia , Camundongos , Camundongos Endogâmicos CBA , Mutação , Parasitemia/genética , Piruvato Quinase/genéticaRESUMO
To investigate the effect of caspase-12 deficiency on IFN-γ- independent control of blood-stage malaria, we compared lethal Plasmodium yoelii 17XL infection in wild-type C57BL / 6J and caspase-12-/-mice. Infected caspase-12-/- mice exhibited higher parasitaemia than WT mice on days 8 and 9 post-inoculation, but all WT and caspase-12-/- mice succumbed by day 10. In addition, infected caspase-12-/-mice had significantly elevated levels of IFN-γ, TNF, IL-18,and IL-10 in sera compared to infected WT mice. At the terminal stage of disease, there were no differences in cytokine levels in the tissues of infected WT and caspase-12-/- mice. However, liver pathology was more severe in infected caspase-12-/- mice compared to infected WT mice. Together, these findings indicate that although caspase-12 deficiency results in enhanced pro-inflammatory and immunoregulatory cytokine levels in sera during P. yoelii 17XL infection, these responses are not essential for protection against lethal malaria infection.
Assuntos
Caspase 12/imunologia , Citocinas/sangue , Malária/imunologia , Malária/patologia , Plasmodium yoelii/imunologia , Plasmodium yoelii/patogenicidade , Animais , Caspase 12/deficiência , Feminino , Fígado/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Parasitemia , Análise de SobrevidaAssuntos
Mapeamento Cromossômico , Malária Falciparum/genética , Malária Falciparum/parasitologia , Parasitemia/genética , Plasmodium falciparum , Animais , Cruzamentos Genéticos , Suscetibilidade a Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos A , Camundongos Endogâmicos C57BLRESUMO
Primary infection with the gastrointestinal nematode Heligmosomoides polygyrus bakeri is chronic in C57BL/6 (B6) mice whereas challenge infection is rapidly eliminated. F4/80-CD11b+Gr+ cells, presumed to be neutrophils, were reported to accumulate around encysting larvae in intestinal tissue during primary infection, but their exact identity and role remain unclear. We observed significant increases in F4/80-CD11bhiGr1hi cells in mesenteric lymph nodes (MLNs) and spleen after primary but not challenge infection; a high proportion of these cells expressed Ly6G and Ly6C. These cells, which phenotypically resemble myeloid-derived suppressor cells (MDSC), increased in lamina propria (LP) early during primary infection. Increased MDSC were associated with low numbers of alternatively activated macrophages (AAMØ) in LP and CD4+GATA3+ T cells and AAMØ in MLN and spleen. Purified CD11c-CD11b+Gr1+ cells from H. polygyrus bakeri-infected mice suppressed OVA-specific CD4+ T-cell proliferation via a nitric oxide-dependent mechanism and parasite-specific IL-4 secretion in vitro. Adoptive transfer of CD11c-CD11b+Gr1+ cells from mice with primary infection resulted in significantly higher adult worm burdens and increased egg production in naïve B6 recipients infected with H. polygyrus bakeri. Altogether, these findings indicate that primary H. polygyrus bakeri infection induces a novel subset of MDSC that suppress CD4+ Th2 responses and promote chronic infection.
Assuntos
Células Supressoras Mieloides/imunologia , Nematospiroides dubius/imunologia , Neutrófilos/imunologia , Infecções por Strongylida/imunologia , Células Th2/imunologia , Animais , Antígenos de Helmintos/imunologia , Proliferação de Células , Células Cultivadas , Doença Crônica , Feminino , Tolerância Imunológica , Interleucina-4/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides/parasitologia , Neutrófilos/parasitologia , Carga Parasitária , Células Th2/parasitologiaRESUMO
Accumulating evidence provides strong support for the importance of innate immunity in shaping the subsequent adaptive immune response to blood-stage Plasmodium parasites, the causative agents of malaria. Early interactions between blood-stage parasites and cells of the innate immune system, including dendritic cells, monocytes/macrophages, natural killer (NK) cells, NKT cells, and gamma6 T cells, are important in the timely control of parasite replication and in the subsequent elimination and resolution of the infection. The major role of innate immunity appears to be the production of immunoregulatory cytokines, such as interleukin (IL)-12 and interferon (IFN)-gamma, which are critical for the development of type 1 immune responses involving CD4+ Thl cells, B cells, and effector cells which mediate cell-mediated and antibody-dependent adaptive immune responses. In addition, it is likely that cells of the innate immune system, especially dendritic cells, serve as antigen-presenting cells. Here, we review recent data from rodent models of blood-stage malaria and from human studies, and outline the early interactions of infected red blood cells with the innate immune system. We compare and contrast the results derived from studies in infected laboratory mice and humans. These host species are sufficiently different with respect to the identity of the infecting Plasmodium species, the resulting pathologies, and immune responses, particularly where the innate immune response is concerned. The implications of these findings for the development of an effective and safe malaria vaccine are also discussed.
Assuntos
Eritrócitos/parasitologia , Malária/imunologia , Plasmodium/imunologia , Animais , Anticorpos Antiprotozoários/sangue , Eritrócitos/imunologia , Imunidade Inata , Malária/sangue , Malária/parasitologia , Subpopulações de Linfócitos T/imunologiaRESUMO
The in vitro chemotactic responses of peritoneal macrophages from mice bearing transplantable syngeneic 3-methylcholanthrene-induced tumors in their footpads were depressed to about 50% of normal levels. This chemotactic defect to both lymphocyte- and complement-derived stimuli was evident before the appearance of palpable tumor (within 1 week of tumor injection) and persisted until the death of the animal by 6-8 weeks. Chemotactic depression was not observed with macrophages from mice treated with tissue culture medium, fetal calf serum, incomplete Freund's adjuvant, or syngeneic spleen cells.
Assuntos
Quimiotaxia , Macrófagos/imunologia , Neoplasias Experimentais/imunologia , Animais , Líquido Ascítico/citologia , Proteínas do Sistema Complemento , Endotoxinas/farmacologia , Imunidade , Linfócitos/imunologia , Masculino , Metilcolantreno , Camundongos , Camundongos Endogâmicos C3H , Neoplasias Experimentais/induzido quimicamenteRESUMO
Culture fluids from five murine sarcomas were chemotactic for syngeneic peritoneal macrophages in vitro. Peritoneal macrophages from mice infected with Mycobacterium bovis, strain Bacillus Calmette-Guérin, were more responsive to the chemotactic factor in tumor cultures than were normal macrophages. Peritoneal granulocytes, however, did not significantly respond to this factor. The level of chemotactic activity in tumor cultures paralleled cell growth for all five tumors; maximal levels occurred during log growth. Culture medium alone or fluids from proliferating spleen cell cultures stimulated with mitogens did not have detectable chemotactic activity. Chromatography of the tumor culture fluids resulted in a single peak of chemotactic activity in the 15,000-molecular weight range on Sephadex G-100 and at about 7.5 mmho/cm specific conductance on diethylaminoethyl cellulose. By both biological and physicochemical characteristics, the chemotactic activity in tumor culture fluids was different from mouse lymphocyte-derived chemotactic factor.
Assuntos
Quimiotaxia , Linfócitos/imunologia , Macrófagos/imunologia , Sarcoma Experimental/imunologia , Animais , Líquido Ascítico/citologia , Divisão Celular , Células Cultivadas , Quimiotaxia de Leucócito , Meios de Cultura , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C3H , Sarcoma Experimental/metabolismo , Sarcoma Experimental/patologiaRESUMO
Examination of the proliferative responses in vitro to mitogens (concanavalin A, phytohemagglutinin, lipopolysaccharide) of spleen cells recovered from C57BL/6 mice during blood-stage Plasmodium chabaudi AS infection revealed that the most severe suppression occurred during the first 14 days post infection, that is, during the acute phase of infection. Coincidently, inducible nitric oxide synthase gene expression was found to be up-regulated in the spleens of infected mice, and both splenic and peritoneal macrophages produced high levels of NO in vitro in response to stimulation with lipopolysaccharide (LPS). The roles of NO, a molecule recently found to mediate immunosuppression during parasitic infections, and of the well-recognized immunosuppressive molecule prostaglandin were, therefore, investigated in the suppression of proliferation to mitogens and specific antigen of spleen cells from 7- and 14-day P. chabaudi AS-infected mice. Addition of either 0.5 mM NG-monomethyl-L-arginine (L-NMMA) or 0.5 mM aminoguanidine (AG), inhibitors of NO synthase, or 10 micrograms/ml indomethacin (INDO), a prostaglandin inhibitor, partially but significantly abrogated the suppression in response to concanavalin A (Con A) and phytohemagglutinin (PHA). Only the addition of INDO significantly increased the responses to LPS. Addition of L-NMMA or AG in combination with INDO partially but significantly abrogated the suppression in response to Con A and completely abrogated the suppression in response to PHA. The addition of L-NMMA or AG also significantly increased proliferation in response to parasite antigen. The contribution of NO to suppression of lymphoproliferation was confirmed by adding 3-morpholino-sydnonimine-hydrochloride (SIN-1), a chemical generator of NO, to mitogen-stimulated splenocyte cultures prepared from normal mice. The mechanism of NO-mediated suppression was investigated in coculture experiments using spleen cells from normal mice and peritoneal macrophages from either normal or day 7 infected mice. The addition of 5-10 x 10(4) peritoneal macrophages from infected mice significantly and consistently suppressed Con A- or PHA-stimulated proliferation of normal splenocytes. Moreover, suppression correlated with production of NO and could be reversed by the addition of L-NMMA or AG. These results suggest that, in addition to prostaglandin, increased NO production by macrophages within the first 2 weeks after infection with P. chabaudi AS contributes to immunosuppression associated with blood-stage malaria.
Assuntos
Ativação Linfocitária , Macrófagos Peritoneais/imunologia , Malária/imunologia , Óxido Nítrico/fisiologia , Aminoácido Oxirredutases/biossíntese , Animais , Arginina/análogos & derivados , Arginina/farmacologia , Sequência de Bases , Primers do DNA/química , Feminino , Guanidinas/farmacologia , Tolerância Imunológica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Óxido Nítrico Sintase , Plasmodium chabaudi , Prostaglandinas/fisiologia , Baço/citologia , ômega-N-MetilargininaRESUMO
The in vivo role of interleukin (IL)-12 in correcting anemia and the underlying defect in erythropoiesis in Plasmodium chabaudi AS-susceptible A/J mice was examined. Six daily intraperitoneal injections of 0.1 microg IL-12 in A/J mice, beginning on the day of infection, rapidly and significantly enhanced bone marrow and splenic erythropoiesis as demonstrated by marked increases in early and late committed erythroid progenitors, the erythroid burst (BFU-E) and colony-forming units (CFU-E), respectively, compared with control mice. The most dramatic effect of IL-12 treatment was a sevenfold increase in the number of splenic CFU-E on day 7 postinfection, compared with untreated, infected A/J mice. Treatment with IL-12 also caused significant increases in hematocrit levels, erythrocyte counts, percentage of reticulocytes, spleen cellularity, and frequencies of BFU-E and CFU-E in the bone marrow and spleen of A/J mice during infection. The frequency of BFU-E in the peripheral blood of these mice was also significantly increased, suggesting enhanced mobilization of precursor cells to the spleen as well as increased production of erythroid precursors in this organ. Consistent with previous observations using higher doses, 0.1 microg IL-12 administered daily for 6 days to normal A/J mice significantly decreased bone marrow erythropoiesis and significantly increased splenic erythropoiesis. However, the influence of IL-12 on erythropoiesis was much more pronounced during ongoing malaria infection. These results suggest a role for IL-12 during blood-stage malaria in not only enhancing the development of protective immunity but also in alleviating malaria-induced anemia by increasing the number of erythroid precursors and enhancing the expansion of committed erythroid progenitors.
Assuntos
Anemia/tratamento farmacológico , Interleucina-12/uso terapêutico , Malária/tratamento farmacológico , Plasmodium chabaudi , Animais , Suscetibilidade a Doenças , Injeções Intraperitoneais , Interleucina-12/administração & dosagem , Malária/sangue , Camundongos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêuticoRESUMO
This review focuses on the role of interleukin (IL)-12, a proinflammatory cytokine with pleiotropic effects as a potent immunoregulatory molecule and hematopoietic growth factor, in infection with Plasmodium parasites, the causative agents of malaria. IL-12 has been demonstrated to have profound effects on the immune response to blood-stage malaria, to induce protection, and to alleviate malarial anemia. In combination with an anti-malarial drug, IL-12 is effective in an established malaria infection. This cytokine also has potent immune effects as a malaria vaccine adjuvant. However, IL-12 can also mediate pathology during blood-stage malaria.
Assuntos
Interleucina-12/uso terapêutico , Malária/terapia , Adjuvantes Imunológicos , Anemia/etiologia , Anemia/imunologia , Animais , Modelos Animais de Doenças , Humanos , Imunidade Ativa , Interleucina-12/imunologia , Malária/complicações , Malária/prevenção & controle , Camundongos , Plasmodium , Vacinas Protozoárias/uso terapêuticoRESUMO
The functional state of the mononuclear phagocyte system has been investigated in mice undergoing chronic graft-versus-host (GVH) reactions (GVHR), initiated by the injection of parental DBA/2 lymphoid cells into (DBA/2 X C57BL/6)F1 hybrid mice. Macrophage function was assessed in vivo by the ability to develop host resistance to infection with Listeria monocytogenes and found to be normal in GVH mice, as measured by the development of resistance during the early phase of natural (macrophage-mediated) resistance to the infection. During the later phase of acquired immunity to listerial infection, GVH mice had lowered resistance, but this was attributed to impaired T cell immunity rather than to defective macrophage function. The inflammatory response to a phlogistic agent, thioglycolate, was also found to be normal in GVH mice, as measured by the accumulation of inflammatory macrophages in the peritoneal cavity. In an in vitro assessment of macrophage function, phagocytosis was found to be enhanced initially (2 weeks following GVHR induction) but it subsequently became depressed for the duration of the study (12 weeks after GVHR induction). Macrophage chemotactic activity was initially normal, then became depressed and remained so for the duration of the study. Thus, despite the profound suppression of specific immunity induced by the GVH reaction and the functional defects of GVH macrophages apparent in vitro, the response of the mononuclear phagocyte system to in vivo stimuli, such as infection or inflammation, is unimpaired in GVH mice.
Assuntos
Reação Enxerto-Hospedeiro , Macrófagos/imunologia , Animais , Feminino , Técnica de Placa Hemolítica , Tolerância Imunológica , Imunidade Inata , Cinética , Listeria monocytogenes/imunologia , Listeriose/imunologia , Masculino , Camundongos , Camundongos Endogâmicos DBA , Camundongos EndogâmicosRESUMO
The contribution of the T cell- and macrophage-derived cytokines, interferon-gamma (IFN-gamma) and tumor necrosis factor (TNF), respectively, in the cell-mediated mechanisms leading to acquired immunity to blood-stage Plasmodium chabaudi AS was investigated. To examine the contribution of IFN-gamma, resistant C57BL-derived mice were treated during infection with two different neutralizing, anti-murine IFN-gamma mAbs. Such treatment impaired the ability of the host to limit parasite multiplication just before and at the time of the peak parasitemia but did not abrogate the development of acquired immunity resulting in control and elimination of acute infection. The requirement of endogenous IFN-gamma around the time of the peak parasitemia was confirmed by quantification of IFN-gamma production in vitro by spleen cells from infected animals in response to malaria antigen. To investigate the role of TNF, resistant C57BL/6 and susceptible A/J mice were treated with rTNF during P. chabaudi AS infection. Treatment with 10(3) or 10(5) U rTNF resulted in increased resistance in A/J hosts (that is, increased survival and a less severe course of infection); there was no difference between control and treated C57BL/6 mice in the course of infection but there was increased mortality among the animals treated with rTNF. Splenic macrophages harvested from C57BL/6 mice during infection were found to produce high levels of TNF from day 3 to day 28 post-infection. In conclusion, both IFN-gamma and TNF appear to contribute to host resistance to blood-stage infection with P. chabaudi AS.
Assuntos
Interferon gama/fisiologia , Malária/imunologia , Fator de Necrose Tumoral alfa/fisiologia , Animais , Ensaio de Imunoadsorção Enzimática , Imunidade Inata/fisiologia , Interferon gama/biossíntese , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Recombinantes/farmacologia , Baço/metabolismo , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
Trypanosoma musculi obtained from normal or irradiated (900 rad) hosts or from in vitro cultures were lysed and analysed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). Similar protein banding patterns with a molecular weight (mol. wt) range from 34 to 68 kDa were observed between the two bloodstream forms. In comparison, lysates of cultured parasites showed a unique banding pattern of antigens within the same mol. wt range. Western blot of bloodstream form lysates, probed with immune plasma (IP), revealed a wide range of parasite proteins. However, when probed with the IgG2a-enriched fraction of IP, a major band of approximately 66 kDa was detected on the blot. Several bands of higher mol. wt were also observed. When anti-T. musculi monoclonal antibodies were used to probe the blot, the 66 kDa protein was again recognized. Using indirect fluorescence, live bloodstream form parasites were analysed by flow cytometry and the p66 protein was determined to be a surface molecule. Finally, lysates of 35S-methionine-labelled trypanosomes were immunoprecipitated with Sepharose linked anti-T. musculi monoclonal antibodies and the eluted ligand analysed by SDS-PAGE and autoradiographed. The 66 kDa band was identified, therefore confirming that this protein was of parasite origin.
Assuntos
Anticorpos Monoclonais/imunologia , Antígenos de Protozoários/análise , Imunoglobulina G/imunologia , Trypanosoma/imunologia , Animais , Antígenos de Protozoários/imunologia , Eletroforese em Gel de Poliacrilamida , Feminino , Immunoblotting , Masculino , Camundongos , Testes de PrecipitinaRESUMO
In a previous pilot study that did not reach statistical significance, intermittent single-leg pneumatic compression appeared effective in reducing the incidence of calf vein thrombosis not only in the pumped calf but also in the unpumped leg in 37 patients, using the 125I-fibrinogen (Abbott Laboratories) technique. The present study was undertaken to investigate mechanical induction of local and systemic fibrinolysis. The euglobulin lysis time in the arm venous effluent was determined in five volunteers before and after unilateral arm compression for 1/2 hour. Shortening averaged 19% (not significant). The experiment was repeated using bilateral calf-length boots with femoral vein sampling. Euglobulin lysis decreased 22% (P < 0.001). To uncover possible systemic effects, the protocol was altered using calf boots with sampling from the arm. The euglobulin lysis diminished 6% in 57 volunteers (P < 0.001). In 27 others the effects of thigh-length and calf-length boots were compared. In half, pumping with a short boot was undertaken first, and in the remainder, the long boot was applied initially. One-half hour of pumping was followed by 1/2 hour of rest. Immediately afterward the second period of pumping took place and continued for 1/2 hour. A total of four arm vein samples were obtained, one before and after each pumping period. Although, in retrospect, the 1/2-hour rest period was inadequate to permit the subjects to return to basal conditions, statistically significant decreases in euglobin lysis time (P = 0.05) occurred with the long boots. This study shows intermittent calf compression increases fibrinolytic potential locally and this effect can be demonstrated systemically. The greater the volume of tissue compressed, the greater the response. The efficacy of intermittent venous compression in reducing the incidence of deep venous thrombosis may be due, in part, to localized induction of fibrinolysis.
Assuntos
Tromboflebite/prevenção & controle , Adulto , Idoso , Equipamentos e Provisões , Fibrinólise , Humanos , Perna (Membro) , Pessoa de Meia-Idade , PressãoRESUMO
Selective deficiency of serum IgA is the most common immunodeficiency in humans; when immunodeficient individuals receive blood transfusions a severe anaphylactoid reaction can develop. The present report describes such a patient. After the transfusion reaction a hemagglutination inhibition assay revealed that her blood contained less than 1.0 micrograms/ml of IgA and an anti-IgA antibody that reacted with the 2 IgA proteins, isotypes IgA1 and IgA2. Immediately after the reaction the patient's serum anti-IgA antibody titer was 1:16,384, and when reevaluated 5 weeks later it was 1:8000. All 3 of her children were shown to be IgA deficient, and 2 of them had antibodies against IgA2. This type of anaphylactoid reaction can be avoided by transfusing blood from IgA-deficient donors, frozen deglycerolized red cells, or red cells that have been washed several times to extract all IgA proteins.
Assuntos
Deficiência de IgA , Reação Transfusional , Adulto , Anafilaxia/tratamento farmacológico , Anafilaxia/etiologia , Bicarbonatos/uso terapêutico , Feminino , Humanos , Síndromes de Imunodeficiência/genética , Infusões Parenterais , Manitol/administração & dosagem , Hemissuccinato de Metilprednisolona/uso terapêutico , GravidezRESUMO
The discovery of the CFTR gene in 1989 has lead to rapid progress in understanding the molecular basis of cystic fibrosis (CF) and the biological properties of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. However, more than 10 years later, recurrent lung infections with Pseudomonas aeruginosa, which lead to chronic lung disease and eventual respiratory failure, remain the major cause of morbidity and mortality among CF patients. A distinguishing feature of lung disease in CF is an exaggerated and persistent inflammatory response, characterized by the accumulation of excessive numbers of neutrophils and dysregulated cytokine production. The events leading to the establishment of lung infection with P. aeruginosa, especially the inflammatory and immunological events, and the relation between the CF defect and infection, remain largely undefined. Progress in this area has been hampered by the lack of a suitable animal model. An exciting achievement in the past few years has been the development of a number of variants of CFTR-deficient mice which exhibit defective cAMP-mediated Cl(-) conductance and have a range of clinical phenotypes from mild to severe. In parallel, a model of chronic P. aeruginosa lung infection has been established in genetically and immunologically well-defined inbred mouse strains which differ in susceptibility to this infection in the lung. BALB/c mice are resistant, while DBA/2 mice are extremely susceptible, with high mortality within 3 days of infection. C57BL/6 and A/J mice are relatively susceptible and experience low mortality. Furthermore, the bacterial load correlates with the magnitude and quality of the inflammatory response in the infected lungs of BALB/c and C57BL/6 mice. Although results of infection studies in CFTR-deficient mice have been variable, C57BL/6-Cftr(m1UNC)/Cftr(m1UNC) knockout mice compared to littermate control mice are highly susceptible to chronic P. aeruginosa infection in the lung. The availability of CFTR knockout mice and non-CF inbred mice differing in susceptibility to chronic P. aeruginosa infection offers useful tools for progress in understanding the genesis of chronic P. aeruginosa infection and the ensuing inflammation in the CF lung, as well as the relation between the CF defect and infection. Information generated from these studies will provide the rationale for the development of novel immunomodulatory measures capable of ameliorating or modulating the chronic inflammation associated with CF lung disease.
Assuntos
Fibrose Cística/complicações , Modelos Animais de Doenças , Pneumopatias/etiologia , Infecções por Pseudomonas/etiologia , Pseudomonas aeruginosa , Animais , Doença Crônica , Fibrose Cística/imunologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Citocinas/metabolismo , Previsões , Pulmão/patologia , Pneumopatias/microbiologia , Camundongos , Camundongos Knockout , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/isolamento & purificaçãoRESUMO
Pelvic infection is the commonest complication of legal abortion. The presence of lower genital tract infections increases the risk of complications, and women requesting abortion are at significant risk of harbouring sexually transmitted diseases (STD). Prophylactic antibiotic treatment can decrease the rate of post-abortal sepsis, but the optimum regime is unclear. In particular, patients with Chlamydia trachomatis infection, and bacterial vaginosis would appear to be at increased risk, and detection and treatment of these conditions can lower this risk. The opportunity to screen and treat for STD presents itself in this setting, allowing patients and their sexual contacts to benefit, with a decrease in the infected pool in the community.
PIP: Induced abortion is one of the most frequent surgical procedures in the UK. Even though it is considered safe, it sometimes has complications and long-term sequelae. Pelvic inflammatory disease (PID) is the most prevalent complication and can lead to chronic pelvic pain, pain during intercourse, infertility, and a higher risk of ectopic pregnancy. Chlamydia trachomatis is perhaps the leading etiologic agent for PID among women who have undergone induced abortion and who develop PID. Gonorrhea is another major etiologic agent for PID. Strategies used to try to reduce pelvic infection revolve around administration of antibiotic prophylaxis based on demographic features and on the presence of certain organisms in the genital tract that may increase their risk (e.g., C. trachomatis and Neisseria gonorrhoeae) and universal antibiotic prophylaxis for all women undergoing abortion. Most of the literature suggests that antibiotic prophylaxis does provide some protection against PID but does not clearly indicate who should be screened and for which pathogens and who should be treated and with which antibiotics. Demographic features useful for identifying who should receive antibiotic prophylaxis are: a history of PID, single status, nulliparity, and youth (especially reliable for chlamydial infection). Screening for bacterial vaginosis involves diagnosis based on 3 of 4 criteria: characteristic vaginal discharge, positive amine test, raised vaginal pH, and the presence of clue cells on microscopy of wet or stained preparations of vaginal discharge. Since C. trachomatis is the most important pathogen, drugs sensitive to it should be administered: tetracyclines and erythromycin. Screening women seeking abortion for sexually transmitted diseases (STDs) provides an opportunity to educate them about STDs and treatment compliance and to contact their partners for investigation, treatment, and contact-tracing to reduce the STD-infected pool in the community.
Assuntos
Aborto Legal/efeitos adversos , Antibioticoprofilaxia , Doença Inflamatória Pélvica/prevenção & controle , Infecções Sexualmente Transmissíveis/prevenção & controle , Feminino , Humanos , Programas de Rastreamento , Doença Inflamatória Pélvica/epidemiologia , Doença Inflamatória Pélvica/etiologia , Gravidez , Prevalência , Fatores de Risco , Infecções Sexualmente Transmissíveis/epidemiologia , Infecções Sexualmente Transmissíveis/etiologiaRESUMO
Over 11 million units of red blood cells are transfused each year in the United States at a cost of over $2 billion. This paper reviews the indications for and the risks of red blood cell transfusions, and provides guidelines for transfusions in both surgical and non-surgical settings.