Tuftsin deficiency in AIDS

doi:10.1016/0140-6736(91)93331-3

The Lancet

Volume 337, Issue 8732, 5 January 1991, Pages 12-13

https://doi.org/10.1016/0140-6736(91)93331-3 Get rights and content

Abstract

Tuftsin is an endogenous tetrapeptide that stimulates phagocytosis and is released from the Fc fragment of IgG by a splenic endocarboxypeptidase. Tuftsin activity and splenic function were measured in 21 patients with AIDS, 7 patients with AIDS-related complex (ARC), 22 patients who had undergone splenectomy, and 37 healthy volunteers. There was a significant inverse correlation between tuftsin activity and splenic function in all subjects. Tuftsin activity was significantly lower in patients with AIDS, ARC, and in those who had undergone splenectomy compared with healthy volunteers. Tuftsin deficiency may contribute to the risk of bacterial infection in symptomatic HIV-positive individuals.

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Cited by (31)

Microglia activation mediates fibrillar amyloid-β toxicity in the aged primate cortex
2011, Neurobiology of Aging
Citation Excerpt :
Tuftsin has been found to stimulate all functions of phagocytic cells, including phagocytosis, pinocytosis, motility, immunogenic activity, release of potentially toxic substances such as TNF-α, ROS and nitric oxide (NO) and bactericidal activity (Najjar, 1983; Cillari et al., 1994). Consistent with its function, tuftsin deficiency in many disease states is associated with an increased incidence of infections (Corazza et al., 1991; Szkaradkiewicz, 1992; Trevisani et al., 2002). A tripeptide fragment of tuftsin (Thr-Lys-Pro, macrophage/microglia inhibitory factor [MIF]), acts as an immunosuppressant, inhibits microglial activation, abolishes the above effects (Siemion et al., 1994; Wieczorek et al., 1994) and thereby protects neurons in vivo and in vitro from several modes of damage (Kaul and Lipton, 1999; Rogove and Tsirka, 1998; Thanos et al., 1993).
The amyloid-β peptide (Aβ) plays a central role in the pathogenesis of Alzheimer's disease (AD). The fibrillar form of Aβ (fAβ) exerts toxic effects on neurons through mechanisms not well understood. We have shown that the aged primate cortex is selectively vulnerable to fAβ toxicity at low concentrations. In addition to neuronal loss, fAβ induced massive activation of microglia in the aged rhesus cortex. We now demonstrate that inhibition of microglia activation abolishes fAβ toxicity. Injection or pump delivery of macrophage/microglia inhibitory factor (MIF) significantly reduced activation of microglia and the volume of damage caused by fAβ. Microglia isolated from aged rhesus cortex produced substantial reactive oxygen species when stimulated by fAβ, which was inhibited by MIF in a dose-dependent manner. This is the first definitive in vivo demonstration that the fAβ-induced microglia activation and inflammation mediate, at least in part, its toxic effects on neurons. Combined with our earlier observations, these findings suggest that aged primate microglia may display an exaggerated inflammatory response to fAβ when compared with young microglia.
Immunomodulatory potential of hydrophobic analogs of rigin and their role in providing protection against Plasmodium berghei infection in mice
2001, International Immunopharmacology
Here, we report the immunomodulating potential of N-palmitoyl-amino-ethyl-rigin amide (PR) and N-cholestanyl-amino-ethyl-rigin amide (CR), the two new structural analogs of rigin (an IgG-derived tetrapeptide). Their activity profiles are compared with native tuftsin (NT) and/or N-palmitoyl-amino-ethyl-tuftsin amide (PT) taken as positive control. To explore the possibility of their use as targeting molecules, they are incorporated into the liposome bilayer and, subsequently, interacted with macrophages in an in vitro study.
The new analogs of rigin with the hydrophobicity introduced at the C-terminus are found to considerably improve both the cell-mediated and the humoral immune responses in mice. However, unlike tuftsin and its analog, which mainly activate polymorphonuclear leukocytes and macrophages, the rigin analogs appear to manifest their response more through lymphocytes. When administered prophylactically to a group of mice, at the dose of 100 μg/0.5 ml/mouse/day for 2 days (i.v.), followed by a challenge presented with 1×10⁶ rbcs parasitised with Plasmodium berghei on day 0, substantial reduction in parasitaemia and rate of mortality is observed. This led to increase the median survival time (MST) of the treated group in comparison to the control group. The response is found to be more prominent in CR-treated mice possibly because of the presence of steroid moiety, which is likely to have more productive interaction with cell membranes. Incorporation of these peptides into the bilayer of liposomes does not alter the permeability behavior of vesicles and, in fact, enhances their uptake by the macrophages in an in vitro study. The effect, however, is dependent on both, the concentration of peptide liposomes and the time of incubation.
Present study, thus, establishes the possible use of these analogs not only as adjuvant in chemotherapy, but also as a prophylactic supplement to boost the natural immune status. The activity response of rigin analogs is manifested through lymphocytes, they can also find use in the chemotherapy of diseases, like leishmaniasis, tuberculosis and leprosy, where macrophage activity is either tamed or impaired by pathogens.
Tuftsin: On the 30-year anniversary of Victor Najjar's discovery
1999, Peptides
After a short description of the results of Victor Najjar’s research on tuftsin and of the discoveries done by other authors in the early stage of tuftsin investigation, the current state of work on tuftsin is presented, based mainly on the literature published in the years 1984–1997. The presentation follows this order: the occurrence of tuftsin and retro-tuftsin sequences in proteins, their synthesis and biology, the antigenic properties of tuftsin, its influence on phagocytic cells, and other biologic activities of tuftsin, including antimicrobial, antiviral, antitumor and central effects, and the search for tuftsin superactive analogs.
A reassessment of splenic hypofunction in celiac disease
1999, American Journal of Gastroenterology
Objectives: Because there is controversy regarding the prevalence, familial occurrence, and possible factors inducing splenic hypofunction in celiac disease, we have reassessed them in a large series of untreated patients and their first-degree relatives. Methods: Pitted red cell counting was used to measure splenic function and the effect that age at diagnosis has on it, while severity of intestinal lesions and nutritional status were estimated by multiple linear regression analysis. Moreover, serum tuftsin activity was assayed by measuring its ability to stimulate phagocytosis of opsonized Staphylococcus aureus. Results: We found that 32.8% of untreated celiacs and none of their relatives had pitted red cell values in the range of splenic hypofunction (>4%). Only age at diagnosis, but not the other two covariates, was significantly associated with the degree of splenic hypofunction. Tuftsin activity was depressed in celiac disease and this reduction was significantly greater in hyposplenic patients. Conclusions: In celiac disease the prevalence of splenic hypofunction is lower than formerly believed. The duration of preexposure to gluten is a crucial factor for the prevalence and severity of this complication that does not affect celiac relatives. In celiac disease splenic hypofunction is accompanied by a reduced phagocyte activity linked to the decreased release of tuftsin.
Overwhelming postsplenectomy infection
1996, Infectious Disease Clinics of North America
Create her child of spleen; that it may live.
WILLIAM SHAKESPEARE
The Tragedy of King Lear
Understanding splenic function eluded man for more than 2500 years. Hippocrates (460–377 BC) taught that the spleen “drew the watery part of food from the stomach.” Aristotle (384–322 BC) believed that it had no vital function. Pliny, in the first century AD, felt that the spleen's weight might hinder the speed of runners and could be removed “by way of incision,” resulting in the inability to laugh. The ancient Greeks also believed the spleen impaired athletic abilities, and applied hot irons to reduce its size.
Described by Galen (130–200 AD) as the “organ of mystery,” the spleen was later believed to be the source of melancholia (black bile or choler) as the theory of bodily humors arose. This theory persisted more than 1000 years, giving rise to the idea of “venting one's spleen.” In the Babylonian Talmud (second to sixth centuries) and the ancient Jewish writings of Judah Halevi (1086–1145), the notion of the spleen's role in laughter evolved. Because laughter was believed to be a cleansing process, it followed that the spleen “cleanses the blood and spirit from unclear and obscuring matter.” Maimonides (twelfth century) also stressed the spleen's function in purifying blood. The overall image of the spleen, however, was that of a nonessential organ that could be removed without adverse effects. This image persisted until the early 1900s.
In 1919, Morris and Bullock were the first to recognize the spleen's role in infection, based on animal studies, stating: “It is an observation of great antiquity that the operation of splenectomy is not followed by death. Indeed one may live for years without suffering any apparent ill effect from the absence of the organ; but this does not settle the problem as to whether or not a splenectomized person can weather a critical illness.”⁶⁷ Cases of infection in splenectomized hosts were noted but roused little attention, probably because septic death was common. In 1952, King and Shumacker⁴⁸ reported five cases of fulminant sepsis in splenectomized infants. Following this report, the association between splenectomy and fulminant, lethal sepsis has been firmly established, and knowledge of the spleen's role in the response to bacterial infection has expanded.* The evolution from good health to death within 1 day has been repeatedly documented in the asplenic patient. Septic death rates of up to 600 times greater than the general population have been reported for this syndrome of overwhelming postsplenectomy infection (OPSI).6, 90 Despite the large amount of published cases, insufficient data exist to determine the true incidence, exact nature of infection, risk factors, and the contribution of underlying conditions to overwhelming infection in the splenectomized host, a true medical emergency.
Enhanced phagocytosis activity of cyclic analogs of tuftsin
1995, Biochemical Pharmacology
Cyclic analogs of the physiological immunostimulating peptide tuftsin (Thr-Lys-Pro-Arg), cyclo(Thr-Lys-Pro-Arg-Gly) (ctuf-G) and cyclo(Thr-Lys-Pro-Arg-Asp) (ctuf-D), were synthesized based on molecular modeling studies, and assayed for the ability to stimulate phagocytosis by human polymorphonuclear leukocytes. As predicted, the synthesis of ctuf-D resulted in two isomers with the correct molecular mass and amino acid composition. In phagocytosis assays, tuftsin, ctuf-G and two isomers of ctuf-D showed the usual bell-shaped activity profiles. The optimum concentration of ctuf-G was 50-fold less than that of tuftsin, whereas the degree of stimulation was similar. One isomer of ctuf-D was almost inactive, and the other ctuf-D exhibited the same degree of phagocytosis as tuftsin but its optimum concentration was 5-fold lower. The enhanced potency of ctuf-G and one isomer of ctuf-D may be due to conformational effects and/or to the possibility that these cyclic peptides are resistant to proteolytic degradation.

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ORIGINAL ARTICLESTuftsin deficiency in AIDS

Abstract

Am J Med

Biochem Biophys Res Commun

Pathogenesis of infection with human immunodeficiency virus

N Engl J Med

Serious infection after splenectomy for the staging of Hodgkin's disease

Ann Intern Med

Bacterial infection and sickle cell anemia: an analysis of 250 infections in 166 patients and a review of the literature

Medicine (Baltimore)

Tuftsin: a physiological phagocytosis-stimulating peptide

Nature

Defective phagocytosis due to tuftsin deficiency in splenectomized subjects

Am J Dis Child

Decreased serum tuftsin concentrations in sickle cell disease

Arch Dis Child

Tuftsin, a natural activator of phagocyte cells: an overview

Ann NY Acad Sci

Classification system for human T-lymphotropic virus type III/lymphadenopathy-associated virus infections

MMWR

ORIGINAL ARTICLES
Tuftsin deficiency in AIDS