Chronic immune activation associated with intestinal helminth infections results in impaired signal transduction and anergy

Helminthic parasites cause widespread, persistent infections in humans. The immigration of Ethiopians to Israel (a group denoted here by “Eth.”), many of them infested with helminths and in a chronic immune-activation state, enabled us to investigate the effects of such immune activation on immune responses. We studied the immune profile and immune functions of 190 Eth. and Israeli non-Eth. (Isr.) highly, partially, or non–immune-activated individuals. Immune cells from highly immune-activated individuals were defective in several signaling responses, all of which were restored gradually following anti-helminthic treatment. These cells showed poor transmembrane signaling, as seen by the phosphorylation of various tyrosine kinases and of the MAPK kinases, ERK1/2 and p38; deficient degradation of phosphorylated IκBα; increased expression of cytotoxic T lymphocyte–associated antigen 4 (CTLA-4), which appears to block proliferative responses in these cells; decreased β-chemokine secretion by CD8⁺ cells after stimulation; and reduced proliferation to recall antigen stimulation. Highly immune-activated individuals also showed decreased delayed-type skin hypersensitivity responses to recall antigen before deworming. These findings support the notion that chronic helminthic infections cause persistent immune activation that results in hyporesponsiveness and anergy. Such impaired immune functions may diminish the capacity of these individuals to cope with infections and to generate cellular protective immunity after vaccination.

Helminthic infections are common in vast regions of the world, especially in the developing countries, and by the most conservative estimates, they affect more than a quarter of the world’s population (approximately 1.5 billion people) (1). In addition, millions of individuals in the developing countries also have other chronic infectious diseases, such as malaria, tuberculosis (TB), protozoa, and HIV (2, 3). These infections lead to persistent activation of the immune system, and thus vast populations in the globe, especially in Africa and Asia, are in a chronic immune-activation state. However, how chronic immune activation affects the capacity of the immune system to respond to stimuli is not well understood.

During the last 15 years, about 60,000 Ethiopian Jews emigrated from Ethiopia to Israel. A very high prevalence of several infectious diseases, particularly helminthic infections, has been found among the population of Ethiopian immigrants to Israel (denoted here by “Eth.”) (4). More than 80% of the Eth. individuals were infected with at least one helminthic parasite, 40% were infected with two parasites, and some (∼3%) were even infected with four intestinal helminthic parasites. Although Eth. individuals who immigrated 10–15 years ago were not infected with HIV, almost 10% of the Eth. individuals who immigrated during the last year were HIV-1 seropositive (data not shown). All Eth. individuals arrived from areas in which TB is endemic; however, the prevalence of TB was relatively low (<1.5%) (4).

Examination of the immune profile of the HIV-seronegative, Mycobacterium tuberculosis–noninfected members of the Eth. group revealed a wide immune dysregulation characterized by a dominant Th2 type of cytokine immune response, high IgE levels, eosinophilia, low CD4⁺ and high CD8⁺ cells, increased HLA-DR–positive cells in all examined T-cell subsets, decreased proportion of naive CD4⁺ cells, and increased proportion of CD4⁺ memory cells (5–7). This immune dysregulation, caused mainly by helminthic infections (6, 7), is assumed to be widespread in Ethiopia and in other parts of Africa where helminthic infections are endemic. Indeed, similar immune profiles were observed in other populations from Ethiopia (8) and other developing countries (9–13). After their arrival in Israel, most Eth. individuals were cured of the helminthic infections (ref. 14; data not shown) and their immune systems slowly returned to normal (7, 15).

In the present report, we studied the immune-activation status and the capacity of PBMCs to respond to various stimuli in three groups: recently arrived Eth. individuals (new-Eth.) with helminthic infection before deworming, Eth. individuals living in Israel for at least 3 years (old-Eth.) without helminthic infection after anti-helminthic treatment, and healthy noninfected Israeli-born (Isr.) individuals. In the study, we determined (a) expression of costimulatory and downregulatory receptors on T cells (CD28 and cytotoxic T lymphocyte–associated antigen 4 [CTLA-4], respectively); (b) intracellular events that occur immediately after T-cell stimulation (signal transduction); (c) long-term outcome events, such as proliferation after recall antigen stimulation, and β-chemokine secretion by CD8⁺ cells; and (d) delayed-type skin hypersensitivity (DTH) responses to recall antigens.

The results of this study clearly show that chronic immune activation results in hyporesponsiveness, manifested by impaired T-cell signal transduction, significantly lower expression of CD28 with concomitant increased expression of CTLA-4, decreased β-chemokine secretion, low proliferation to recall antigens, and decreased DTH responses.

Immune profile of the studied population. The immune profile of 111 new-Eth., 48 old-Eth., and 31 Isr. individuals (summarized in Table 1) revealed a clear dysregulation of several immune parameters in the new-Eth. group compared with the Isr. group. Such wide dysregulation is similar to that observed previously by us in other new-Eth. individuals (5–7). In contrast, the differences between the old-Eth. group and the Isr. group are not so remarkable (Table 1), demonstrating that the immune profiles of the Eth. individuals return gradually to normal after their immigration to Israel.

Table 1

Immune profile of studied populations

For further analysis, and for the sake of simplicity, we divided the examined individuals into three categories of activation, according to the proportion of HLA-DR⁺ cells within the CD3⁺ cell population and the proportion of CD28⁺ cells within the CD8⁺ cell population. Nonactivated (NA) individuals were defined as those having a normal percentage of HLA-DR⁺/CD3⁺ and CD28⁺/CD8⁺ cells (similar to that of the Isr. group, i.e., <9% HLA-DR⁺/CD3⁺ cells and >40% CD28⁺/CD8⁺). Highly activated (HA) individuals were defined as those having more than 9% HLA-DR⁺/CD3⁺ cells and less than 40% CD28⁺/CD8⁺, whereas partly activated (PA) individuals were defined as those having either HLA-DR⁺/CD3⁺ or CD28⁺/CD8⁺ subsets above or below the normal range, accordingly. All members of the Isr. group were NA, and members of the new-Eth. group were either HA or PA. About 35% of the old-Eth. group were NA, while the rest were still PA.

Correlation between activation, naive and memory cells, expression of CD28 costimulatory molecules, and the number of CD4⁺ cells. We have previously suggested that the decreased CD4 levels and significantly lower CD4/CD8 ratio in the new-Eth. group, compared with the Isr. group, is a consequence of immune activation (5–7). Correlation studies between different immune parameters of the examined Eth. population in the present study strongly supports this hypothesis. For example, individuals with higher percent of HLA-DR⁺CD4⁺ cells had less CD4⁺ cells in the peripheral blood, lower CD4/CD8 ratio, lower percentage of CD28⁺CD8⁺, naive (CD45RA⁺) cells, and higher percentage of memory (CD45RO⁺) cells (Figure 1). Similar correlations between HLA-DR expression on CD8⁺ and CD3⁺ cells and the various immunological markers examined were also found (data not shown).

Figure 1

Correlations between the percentage of HLA-DR⁺CD4⁺ cells and other cell subsets in Eth. individuals. ns, not significant.

Signal transduction studies. Physiological activation of T-lymphocytes requires costimulation through the T-cell receptor/CD3 complex and CD28, which can be mimicked by PMA in combination with Ca²⁺ ionophore (16–18). After such costimulation, a cascade of phosphorylations and dephosphorylations of intracellular protein occurs, which include the MAPK/ERK, p38 (19, 20), and IκBα proteins (13, 14). The IκBα, once phosphorylated, are degraded by cytoplasmatic proteases, enabling the translocation of NF-κB into the nucleus (21, 22).

To study and characterize the effect of immune activation on T-cell signaling, we isolated PBMCs from 10 NA (Isr. and Eth.), 11 PA (Eth.), and 12 HA (Eth.) individuals and stimulated them with PMA and Ca²⁺ ionophore. At various time intervals after stimulation, cell extracts were prepared and the presence or absence of phosphorylated or nonphosphorylated proteins was examined by Western blots as described in Methods. As shown in some representative examples in Figure 2a, PBMC extracts from all NA Eth. or Isr. individuals revealed strong phosphorylation of ERK isoforms (ERK1 and ERK2) upon stimulation. However, only attenuated phosphorylation of these kinases occurred in seven of 11 PA and in 12 of 12 HA Eth. individuals. The phosphorylation of ERK1 or ERK2 did not increase significantly over time in these examples (data not shown), and in some extreme cases, as shown in Figure 2b, almost no phosphorylation of ERK1 or ERK2 occurred even after prolonged times after stimulation. Moreover, the basal level of the nonphosphorylated ERK kinases, which was significantly higher in the NA Eth. than in the HA Eth. individuals, decreased upon stimulation in accordance with the very strong phosphorylation of ERK1 and ERK2 kinases (Figure 2b). In contrast, in the HA Eth. individuals, the basal levels of the nonphosphorylated ERK 1 did not change after stimulation and insignificant phosphorylation of ERK 1 or 2 occurred even 18 minutes after stimulation (Figure 2b).

Figure 2

Attenuated phosphorylation of ERK1 and ERK2 in chronically immune-activated individuals, as determined by Western blot analysis. PBMC extracts obtained from nonactivated (NA), highly activated (HA), or partially activated (PA) Eth. or Isr. individuals were stimulated for 0 or 6 minutes (a) or for 0, 3, 6, 12, and 18 minutes (b) with PMA and CA²⁺ ionophore. Lysates of these cells were resolved on SDS-PAGE and immunoblotted with anti-phosphorylated p42/44 MAPK/ERK Ab (1:10,000) and anti-BCL2 Ab (1:500). The immunoblot in b was stripped and rehybridized with anti-p42/44 MAPK/ERK Ab (1:10,000). pERK, phosphorylated ERK.

In the case of PBMCs obtained from five Isr. individuals with an NA immune profile, the IκBα proteins were degraded after cell stimulation as expected (Figure 3a). However, in PBMCs of the four HA Eth. individuals examined, the IκBα proteins were not degraded, although they were partially phosphorylated after the cell stimulation (Figure 3a). Similar defective signaling occurred also in the p38 signal transduction pathway, as shown in a representative experiment in Figure 3b. In both NA and HA individuals, even without costimulation with Ca²⁺ ionophore and PMA, we found phosphorylated p38 in Western blot and FACS analyses, probably due to mechanical stress during the isolation of the cells. Nevertheless, fifteen minutes after the Ca²⁺ ionophore and PMA costimulation, no phosphorylated p38 was observed in five Isr. individuals examined (Figure 3b), indicating dephosphorylation by intracellular phosphatases. In contrast, no dephosphorylation of p38 kinase occurred in all five HA Eth. individuals examined (Figure 3b). In some experiments, as shown in a representative case in Figure 3c, only slight p38 phosphorylation occurred in the cell extracts from HA Eth. individuals; but in any case, no changes were noted after the cell costimulation by Ca²⁺ ionophore and PMA in these samples. Hence, we did not note p38 phosphorylation or dephosphorylation in the case of the HA Eth. individuals.

Figure 3

Impaired activation of IκBα and p38 in highly immune-activated individuals. PBMC extracts obtained from nonactivated (NA) Isr. and highly activated (HA) Eth. individuals were stimulated for 0 or 15 minutes with PMA and CA²⁺ ionophore. Lysates of these cells were resolved on SDS-PAGE and immunoblotted with (a) anti-IκBα (1:2,500) or with (b) anti-diphosphorylated p38 MAP kinase (1:1,000). (c) Kinetic analyses of the changes in p38 phosphorylation and dephosphorylation after stimulation. The cells were stimulated with PMA and CA²⁺ ionophore for 0, 3, 6, or 12 minutes. As control, we activated jurkat cells.

Analyses of the phosphorylation of phosphotyrosine kinases revealed a similar pattern of hyporesponsiveness in ten HA and PA Eth. individuals examined, as opposed to ten NA Eth. and NA Isr. individuals examined. In the case of NA individuals, a clear decrease of phosphorylated kinases was noted 3 minutes after the cell stimulation; thereafter, phosphorylated kinases continued to decrease in a somewhat lower rate. No such decrease was noted in the cell extracts obtained from activated individuals, indicating that they did not respond to the stimuli (Figure 4).

Figure 4

Differential changes in tyrosine phosphorylation in chronically immune-activated individuals compared with nonactivated controls. The patterns of tyrosine phosphorylation in PBMC cells were determined at various times after stimulation of the cells with PMA and CA²⁺ ionophore. Although after stimulation, clear changes in the tyrosine phosphorylation pattern occurred in NA individuals, no significant changes were noted in the activated individuals.

β-Chemokine secretion of CD8⁺ cells after stimulation by phytohemagglutinin and PMA. The above signal transduction studies indicated altered capacity of PBMC obtained from immune-activated individuals to respond to stimuli, such as costimulation with Ca²⁺ ionophore and PMA. Measurement of β-chemokine secretion by CD8⁺ T cells stimulated for 48 hours with PMA and phytohemagglutinin (PHA), revealed a significantly lower secretion of RANTES and MIP-1α from cells obtained from 23 HA and PA Eth. individuals than from cells obtained from 16 Isr. individuals (27.8 ± 11.9 ng/ml vs. 78.1 ± 46.7 ng/ml of RANTES secretion; P < 0.0001; and 95.5 ± 38.3 ng/ml vs. 137.7 ± 48.9 ng/ml of MIP-1α secretion; P < 0.02).

Increased intracellular pool of CTLA-4 in the Eth. group. CTLA-4 is a CD28 homologue that serves as a negative regulator of T-cell responses (23, 24). Binding of B7 to CTLA-4 inhibits the CD28-dependent IL-2 production and proliferation (23, 25). Furthermore, ligation of CTLA-4 receptor by B-7 selectively shuts off activation of downstream T-cell receptor/CD28 signaling events, such as activation of ERK and JNK kinases (26). Resting memory cells, but not naive cells, contain intracellular supplies of CTLA-4 that are continuously recycled between the cytoplasm and the cell surface, raising the cells threshold for costimulatory signals (24). As PBMCs obtained from immune-activated Eth. individuals had decreased capacity to respond to stimuli, we examined whether they have increased expression of CTLA-4. Indeed, a comparison between CTLA-4 expression in 13 PA and HA Eth. and 24 NA Isr. subjects revealed significantly higher expression of CTLA-4 in the Eth. than in the Isr. subjects (8.47 ± 1.97% vs. 5.29 ± 2.47% CTLA-4⁺CD4⁺ cells, respectively; P = 0.03).

PBMC proliferation after stimulation with PPD, a recall antigen. On the basis of the fact that Eth. individuals lived in areas endemic to TB, we examined the capacity of PBMCs obtained from activated and nonactivated Eth. individuals to proliferate after stimulation with PPD, a TB-specific antigen. As shown in Figure 5a, there is a significant, although weak, inverse correlation between the capacity of the cells to proliferate following PPD stimulation and the percentage of HLA-DR⁺/CD3⁺ cells. It should be noted that in all cases in which PBMCs were obtained from HA Eth. individuals, they proliferated poorly after PPD stimulation, and significantly less than in all other Eth. or PA individuals (P < 0.001 and P = 0.038, respectively, according to the Mann-Whitney rank sum test). Those that were able to respond significantly to the recall antigen were either NA or PA Eth. individuals.

Figure 5

(a) Diminished proliferation to PPD antigen by cells obtained from HA individuals. PBMCs were incubated for 6 days with or without 5 μg/ml PPD and then pulsed with [³H]thymidine. The log of SI (stimulation index: incorporation of [³H]thymidine in the presence of PPD divided by the amount of [³H]thymidine incorporated in the presence of medium alone) is plotted against the log of percentage of HLA-DR expression on the CD3⁺ cells. (b) Enhancement of proliferation to PPD after blockage of CTLA-4. PBMCs were stimulated with PPD (as in a, above) in the presence of 0.13 μg (0.66 μg/ml) Fab mAb against CTLA-4 or matched Fab isotype mAb control. The stimulation index results are the average of triplicates.

As CTLA-4 was elevated in Eth. compared with Isr. subjects (see earlier discussion), and as CTLA-4 is a negative regulator of T-cell responses (23, 24) and upregulates the cell’s threshold for costimulatory signals (24), we examined whether blocking of CTLA-4 with Fab mAb would enhance the proliferative responses to PPD of PBMCs obtained from Eth. subjects. Indeed, as depicted in Figure 5b, PBMCs obtained from seven of eight Eth. subjects proliferated significantly more strongly to PPD in the presence of Fab mAb against CTLA-4.

DTH responses after intracutaneous PPD skin injections. DTH responses are part of the cell-mediated immunity. To study further the effect of immune activation on cell-mediated immunity, DTH responses to PPD intracutaneous injection (Mantoux), were examined in 39 HA or PA Eth. individuals, heavily infested with helminthic parasites, before and 6 months after receiving anti-helminthic treatment (albendazole). In addition, the presence of parasites in their stool was examined at both time points. Importantly, the DTH-positive responses to PPD in those individuals in whom the helminths were eradicated increased significantly after deworming, as opposed to those in whom the helminths were not eradicated (P < 0.004, McNemar’s χ² test).

Millions of individuals in the developing countries, especially in Africa, Southeast Asia, and South America, are infested with chronic infectious diseases, such as malaria, TB, protozoa and helminthic parasites, and HIV (1–3). The constant and lifelong confrontation of these hosts with such infectious burden results in a chronic immune activation and unbalanced immune state (5, 11, 27, 28). We have suggested that the capacity of such individuals to protect themselves and to cope with infections, as well as to mount protective immunity after vaccination, is highly impaired (5, 27).

The results of the present work strongly supports these suggestions by showing that chronic immune activation leads to hyporesponsiveness and anergy. This was manifested in highly immune-activated individuals by (a) defective or lacking of early transmembrane signaling (phosphorylation and/or dephosphorylation of tyrosine kinases), suggesting malfunction of both kinases and phosphatases; (b) lack of degradation of phosphorylated IκBα, indicating reduced or malfunction of a cellular protease(s); (c) lack or attenuated phosphorylation of downstream kinases, such as ERK and p38; (d) increased expression of CTLA-4, a downregulator protein; (e) decreased β-chemokine secretion of CD8⁺ cells after stimulation; (f) reduced capacity to proliferate after recall antigen stimulation; (g) restoration of proliferative responses after CTLA-4 blocking; and (h) decreased DTH responses to recall antigen before deworming. These attenuated responses were not a reflection of slower kinetics, but represented significantly diminished responses. Hyporesponsiveness did not occur in only one signal transduction pathway, but in all those that we examined, indicating that this phenomena is a more general cell deficiency.

In concordance with these results are the following observations made by others: defective T-cell signaling occurs in patients with primary intracranial tumors (29); patients with malignant glioblastomas exhibit T-cell anergy (30); anergic Th1 murine cells have decreased p38 and ERK/MAPK activities, even though the levels of these proteins remain unchanged (31–33); and murine anergic CD4⁺ T cells are defective in their ability to upregulate protein binding and transactivation of the NF-AT and AP-1 transcription factors (34, 35).

T-cell receptor stimulation in the absence of CD28-mediated costimulation not only results in little IL-2 production, but induces a long-lasting hyporesponsive state known as T-cell clonal anergy (36). We have already found in several cohorts of Ethiopian immigrants to Israel that CD28⁺ expression on CD8⁺ cells was significantly reduced (5–7, 37). Also in the present work, the new- and old-Eth. cohorts studied had 30% and 10% lower expression of CD28⁺CD8⁺ cells, respectively, than did the Isr. group. This lower expression of CD28⁺ on CD8⁺ cells was negatively correlated with HLA-DR expression in all T-cell subsets. Clearly, the reduced expression of this important costimulatory molecule in T cells in chronically immune-activated individuals is detrimental to their capacity to mount immune responses.

Worsening the situation is the finding that the new-Eth. individuals studied had significantly less CD4⁺ cells, less naive (CD45RA⁺) cells, more memory (CD45RO⁺) cells, and increased CTLA-4 expression on CD4⁺ cells than did the Isr. cohort. This is in accordance with our previous findings with other Eth. cohorts studied (5–7, 37). These differences were correlated with the activation of the individuals (as manifested by the percentage of T cells expressing the surface marker HLA-DR). Clearly, the diminished number of CD4⁺ cells and the lower percentage of naive cells in these individuals lessen their capacity to mount effective immune responses.

A Th2-like immune response with concomitant anergy and downregulation of Th1-associated immunity has been shown in mice infected with a helminthic parasite (38). To our knowledge, this is the first example showing in a human population that constant immune challenge results in a wide immune dysregulation, a predominant Th2 type of cytokine profile, and a clear impairment in the capacity of their cells to respond to stimuli. Taken together, our study strongly supports the idea that chronic immune activation leads to hyporesponsiveness and deficiency of the immune cells, and in some extreme cases to anergy, endangering not only the capacity of these individuals to cope with infection but with their capacity to mount an effective immune response after vaccination.

Several other observations also lend further support to this notion; for example (a) the very high incidence of TB in Africa despite the wide Bacillus Calmette-Guerin (BCG) vaccination carried out in this continent (39, 40); (b) the faster HIV disease progression in sub-Saharan Africa compared with the Western world (41, 42); (c) increased HIV plasma viral load, observed in helminth-infested regions in Africa (43), which was associated with Leishmaniasis and decreased after its treatment (44, 45); (d) human individuals, chronically infected with the filarial parasite Onchocerca vulvurus, have depressed cellular reactivity in vitro and deficient production of IL-2 in response to O. vulvurus–specific antigenic stimulation (46); and (e) humans infected with Schistosoma mansoni have impaired tetanus toxoid-specific immune responses (47).

It should be noted that the expression of CD28⁺ on CD8⁺ cells, the CD4/CD8 ratio, and the percentage of naive and memory cells, as well as the in vitro capacity to respond to stimuli, returns gradually to normal in Eth. individuals living for prolonged periods in Israel. Obviously, the change in environment, the better health care, nutrition, and so forth, and most importantly the eradication of the helminthic parasites, with which more than 80% of the new-Eth. immigrants were afflicted, contributed to this improvement in the immune system of these individuals.

It is believed that generation of HIV- or M. tuberculosis–specific cellular immunity by a vaccine, via a Th1 immune response, is a major prerequisite for any protective HIV or M. tuberculosis vaccine (48–50). The highest incidence of both M. tuberculosis and HIV infections are in Southeast Asia and Africa (2, 3). It is clear that the efficacy of HIV and TB candidate vaccines will have to be tested in human field trials that can only take place in Africa and Asia, in areas with a high incidence of HIV and M. tuberculosis infections. However, potentially good vaccines may fail in such clinical trial if examined in the immune scenario presently existing in the developing world. It is quite clear that the host immune background in developing countries is biased toward a Th2 profile and that most individuals are in a chronic immune-activation state, similar to that which we have seen in the Eth. group. Our findings that signal transduction in such individuals is impaired and that their immune cells can respond poorly to stimuli, such as to PPD, suggest that their capacity to elicit an immune response after vaccination will be heavily encumbered. The failure of BCG vaccination in Africa and Asia to confer protective immunity to TB clearly supports this assumption. It therefore becomes essential to take this major issue into consideration for any protective vaccine development. The simplest and most effective way to do so is by eradication of helminthic infections before or during vaccination. Such eradication is important by itself and has clear advantages and benefits regardless of the issue of HIV and TB vaccination, such as the capacity to cope with infections, the capacity to learn, and so on. We suggest that deworming will have a huge impact on the capacity of individuals in the developing world to cope with disease, and more importantly, we believe that without eradication of helminths, HIV and TB vaccines, and probably others, may fail to confer protection in helminth endemic areas.

The work was supported in part by the grants from The Institute of Advanced Therapy (IAT) for Center of Excellence in AIDS Research in Israel, and the Horowitz Foundation, granted to the Kaplan AIDS Center. A. Kalinkovich is a KAMEA fellow.

Gadi Borkow and Qibin Leng contributed equally to this work.

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