Protective and Nonprotective Antibodies

 

During Chagas’ disease, both protective and nonprotective antibodies are produced. Lytic antibodies (LA) recognize epitopes (specific markers) on the surface of living trypanosomes, attach to these epitopes, and initiate the complement cascade, which includes enzymes that lyse the parasite. Among chronically ill patients, there are varying levels of lytic antibodies. Those patients that show the least clinical manifestations have the greatest number of lytic antibodies that react with epitopes exposed on the surface of living trypanosomes. This explains why acquired immunity from severe symptoms of the acute phase requires the continual presence of living trypanosomes.

The nonprotective antibodies are called CSA (conventional serological antibodies) and do not recognize epitopes of T. cruzi. Patients with the most dramatic clinical manifestations have the greatest number of CSA, which are not inert antibodies but contribute to pathogenesis. Experiments have been performed giving people ground‑up antigens of T. cruzi. These antigens from nonliving T. cruzi organisms induced nonspecific T‑ and B‑cell polyclonal activation and thereby vast amounts of ineffective antibodies that cause more damage to hosts than parasites, similar to what happens to the body in African sleeping sickness and malaria infections.

In this experiment, as well as among chronic patients with severe clinical manifestations, the immune system is being inundated with many different T. cruzi antigens, a few of which are vulnerable targets but the vast majority of which are no more than smoke screens. A person’s humoral immune system produces high levels of anti‑trypanosomal antibodies, but these antibodies are not targeted against epitopes on the surface of living parasites. Rather, these CSA are targeted against antigens that are not important to the parasite, or are unable to be reached, so the CSA are unable to lyse the organism. In popular terms, T. cruzi antigens stimulate polyclonal activation, which is like throwing in a large group of antigens and confusing the system, which then overreacts with too many ineffective punches that do more damage to living cells than to parasites by causing inflammation, fever, and lesions.

The fact that Chagas’ disease patients vary greatly in their proportions of LA and CSA antibodies partially explains the wide range of clinical manifestations exhibited. As already discussed, acute patients with severe symptoms have high levels of CSA and low levels of LA; conversely, those with high levels of LA frequently do not suffer symptoms of the acute phase. This may explain why only about one‑third of infected patients suffer the acute phase. The key variable is how each individual immune system deals with specific surface epitopes of antigens that are important in acting against the parasite. Another factor contributing to the LA/CSA response may be the strain of the parasite; different strains sometimes elicit sharply different antibody responses.

Because low levels of LA correlate with clinical manifestations and because individuals vary in the amount of LA produced, it is important to determine the presence of lytic antibodies in infected patients. ELISA, complement fixation, indirect agglutination tests, and radio immunoassays are not specific enough to distinguish which particular antibody is able to kill T. cruzi. One serological test is complement‑mediated lysis, in which the patient’s serum is bound to trypomastigotes in vitro and exposed to complement. If the complement lyses the parasites, then LA is present in the blood. Indirect immunofluorescence with living trypanosomes is another assay that can determine the protective effect of serum: technicians study antibodies fixed to the surface of living trypanosomes with immunofluorescence to see if they are interacting with epitopes on the surface of the parasite. A third method is serum neutralization, in which living trypanosomes are exposed to a patient’s serum. If the parasite is neutralized, then the serum contains lytic antibodies.

These tests are important to determine a patient’s progress against T. cruzi infection and whether chemotherapy should be used. Patients with low LA levels will not be helped as much by chemotherapy as those whose antibodies are assisting in lysing the parasite. Moreover, as patients are being treated and being cured, LA levels decline rapidly, giving an indication of effective treatment.

This also explains why an active infection is required to stimulate protective immunity: cured patients no longer have LA in their systems. LA are manipulated by parasites so that they are produced at certain times and released under certain circumstances. Parasites regulate their number and degrees of infection in order that overpopulation does not become a problem for their survival and that their hosts remain alive until they can complete their own life cycles.

Also influencing the severity of symptoms, strains and stages of T. cruzi vary in their susceptibility to complement‑mediated lysis. Some strains are lysed more effectively by human complement than are other strains, and the virulence of strains conversely may be related to the parasites’ susceptibility to complement. Regarding T. cruzi stages, blood‑form trypomastigotes are more susceptible than are metacyclic trypomastigotes and intracellular amastigotes. Metacyclic trypomastigotes are initially exposed to complement, and in chickens these parasites are lysed. Metacyclic trypomastigotes quickly go intracellullar, especially into macrophages, where they transform and multiply into amastigote forms. Because of their intracellular location, amastigotes resist complement‑mediated lysis. After several generations, amastigotes transform into trypomastigotes that circulate in the human blood. Not many trypomastigotes are released into the blood; many of them go into cells. These trypomastigotes show a wide variation in their resistance to complement‑mediated lysis, but they are much more susceptible to complement‑mediated lysis in the presence of specific T. cruzi antibodies than are other forms.

 








Дата добавления: 2015-05-16; просмотров: 957;


Поиск по сайту:

При помощи поиска вы сможете найти нужную вам информацию.

Поделитесь с друзьями:

Если вам перенёс пользу информационный материал, или помог в учебе – поделитесь этим сайтом с друзьями и знакомыми.
helpiks.org - Хелпикс.Орг - 2014-2024 год. Материал сайта представляется для ознакомительного и учебного использования. | Поддержка
Генерация страницы за: 0.005 сек.