Home Economics American Trypanosomiasis Chagas Disease, Second Edition: One Hundred Years of Research
Adaptive immune response: the B cell response and production of antibodies
T. cruzi infection is characterized by the production of both parasite-specific and unspecific Ab arising from polyclonal B cell stimulation.154,155 Polyclonal activation is discussed later in this chapter.
Targets of T. cruzi -specific Ab
Molecules of the TS family (expressed by trypomastigotes but not or poorly by amastigotes) are major targets of Ab. The major B epitope is a repetitive sequence called SAPA (shed acute phase antigen). SAPA-repeats induce an early Ab response156 and promotes the production of Ab directed to the catalytic domain that inhibit TS enzyme activity.157 Cruzipain is also strongly immunogenic and elicits Ab.158 Other T. cruzi-specific Ab neutralize parasite molecules involved in parasite—host interaction, like CRP (complement-regulatory proteins),159 T-DAF,160 “TIF” (trypanosomal immunosuppressive factor),161 HSP70,162 the flagellar calcium-binding protein (FCaBP 24 kDa),163 and the adhesion sequence RGD.164 In humans only, Ab directed against a-galactosyl residues abundantly expressed on surface mucins of trypomastigotes strongly increases during infection.165
Isotypes of specific Ab
In human infection, IgA Abs appear first, followed by IgM and IgG. Ab levels peak during the acute phase. IgA and IgM are generally no more detectable in the chronic phase, while IgG persist lifelong in untreated patients. IgG1 subclass predominates among IgG, followed by IgG3. Such isotypes are known to be associated with type 1-responses.166 A similar kinetics is observed in mouse T. cruzi infection, though IgM Ab persist in the chronic phase of the infection (probably related to the short time span as compared to years-long chronic phase in humans).154 In mouse, the IgG specific response is also dominated by an isotype known to be driven by Th1 immune responses, i.e., IgG2a,167 over IgG1 Ab associated with Th2 responses.154
Effector mechanisms of Ab
The production of specific Ab in T. cruzi infection starts rather late. High levels of Ab are reached when parasitemia starts to decrease and there have an important protective role in the transition from acute to chronic phase of infection.168 Mechanisms of clearance of extracellular trypomastigotes by Ab mainly relate to direct lysis of parasites and to phagocytosis of opsonized parasites. These are reviewed elsewhere.3,169 Briefly, some Abs induce complement-dependent lysis of parasites by neutralizing the molecules that protect the parasite against complement lysis,170 while anti-Gal Abs induce lysis of trypomastigotes.6 Anti-a-Gal Ab would however be lytic only before the parasite covers itself very quickly with sialic acid residues that mask a-Gal epitopes, preventing this lysis mechanism.
Ab-opsonized parasites are also eliminated after phagocytosis by activated cells expressing the Fc^R. The Ab isotypes able to bind to these Fc^R, i.e., IgG2a, IgG2b, and IgG1 (in mouse), have a preferential role in parasite clearance.171 Ab-opsonization also leads to deposition of complement components on their membrane, allowing their uptake by phagocytic cells expressing complement recep- tors.172 Macrophages and neutrophils can mediate parasite immune clearance,169 mainly occurring in liver and spleen.173
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