RESUMEN
Protection against the serious complications of falciparum malaria is provided to people with the minor forms of hematological conditions such as sickle cell disease and thalassemia and as a result natural selection has increased their incidence in malaria endemic areas. The explanation for this has thus far not been determined but experimental evidence that is now available suggest an explanation that also has therapeutic implications. The hypothesis presented suggests that the erythrocytes of these blood disorders experience premature senescence and are then eliminated by the same process that normally disposes of senescent erythrocytes. Erythrocytes express approximately one million widely dispersed band 3 molecules on their surface but when these erythrocytes age they form band 3 clusters that are recognized by the immune system which results in their elimination. In addition to senescent erythrocytes, both sickle and falciparum infected erythrocytes also display these clusters suggesting that band 3 antibodies contribute to their erythrocytes removal. Supporting band 3's involvement in falciparum erythrocyte elimination are the facts that band 3 specific antibodies are elevated in falciparum endemic areas and the documentation that the falciparum erythrocytes displaying these clusters are rapidly phagocytized. Both sickle and falciparum infected erythrocytes adhere to endothelium and band 3 antibodies and adhesive band 3 peptides block this adhesion. This proves that the band 3 molecule is responsible for at least some of the endothelial adhesion and implies that band 3 antibodies are active in eliminating falciparum infected erythrocytes. It is proposed that the band 3 peptides could be used to develop a vaccine to reduce the lethality of falciparum infections. A conjugate vaccine using these peptides in early infancy may allow those infants to survive a falciparum infection and develop comprehensive natural immunity to the local endemic parasite.
Asunto(s)
Proteína 1 de Intercambio de Anión de Eritrocito/metabolismo , Proteína 1 de Intercambio de Anión de Eritrocito/uso terapéutico , Eritrocitos/inmunología , Inmunidad Innata/efectos de los fármacos , Vacunas contra la Malaria/inmunología , Vacunas contra la Malaria/uso terapéutico , Malaria/inmunología , Malaria/prevención & control , Modelos Biológicos , Humanos , Vacunas contra la Malaria/síntesis químicaRESUMEN
The major target of the pathogenic red blood cell (RBC) autoantibodies in New Zealand black (NZB) mice is the anion channel protein band 3, and CD4+ T cells from NZB mice respond to band 3. Here, we demonstrate that a band 3 peptide 861-875, which is the predominant sequence recognized by NZB T cells in vitro, bears a dominant helper epitope able to modulate the autoimmune hemolyic anemia in vivo. The development of RBC-bound autoantibodies and anemia was accelerated in NZB mice injected with peptide 861-874, which is relatively insoluble, and inhalation of the peptide primed T cells for both peptide 861-874 and band 3 responses. By contrast, inhalation of a soluble analog (Glu861, Lys875) of peptide 861-874 deviated the autoimmune response toward a T helper-2 (Th2) profile, with marked increases in the ratio of interleukin-4 to interferon-gamma produced by splenic T cells responding in vitro to either peptide 861-874 or band 3. Moreover, in mice that had received such treatment, the proportion of RBC-bound immunoglobulin G (IgG) molecules that were of the Th2-associated IgG1 isotype was also increased, and anemia was less severe. It is concluded that NZB autoimmune hemolytic anemia is helper dependent and that nasal administration of different peptides containing the dominant T-cell epitope can have potentially detrimental or beneficial effects on the disease.
Asunto(s)
Anemia Hemolítica Autoinmune/inmunología , Proteína 1 de Intercambio de Anión de Eritrocito/inmunología , Epítopos de Linfocito T/administración & dosificación , Fragmentos de Péptidos/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/uso terapéutico , Administración por Inhalación , Anemia Hemolítica Autoinmune/terapia , Animales , Proteína 1 de Intercambio de Anión de Eritrocito/uso terapéutico , Autoanticuerpos/biosíntesis , Epítopos de Linfocito T/uso terapéutico , Inmunoglobulina G , Ratones , Ratones Endogámicos NZB , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/uso terapéutico , Solubilidad , Linfocitos T/inmunología , Células Th2/inmunologíaRESUMEN
In this paper, in vivo data are presented that suggest a role for host recognition of erythrocyte band 3 in the control of malaria parasitaemia. The course of Plasmodium chabaudi chabaudi AS acute infection in CBA/Ca mice was suppressed or enhanced as a result of treatment on two occasions with enriched preparations of normal erythrocyte band 3 in adjuvant. Co-treatment with band 3 and a recombinant polypeptide encoding the C-terminal region of the P. c. chabaudi AS merozoite surface protein 1, which on its own had no clear effect on parasitaemia, appeared to modulate band 3-induced inhibition. Despite several-fold reductions in ascending parasitaemias in some band 3-immunized groups, there was a lack of obvious or unexpected anaemia prior to, or during infection, indicating a degree of specificity in the parasitaemia modifying response for infected rather than uninfected erythrocytes. These findings support a role for modified host recognition of erythrocyte band 3 in the partial immunity that transcends phenotypic and genotypic antigenic variation by malaria parasites.