Antiphospholipid antibodies, antiphospholipid syndrome and infections.

Since the association between antiphospholipid antibodies (aPL) and syphilis was first described, many other viral, bacterial and parasitic infections have been shown to induce antiphospholipid antibodies, notably anticardiolipin antibodies (aCL). A review of the literature shows that while aCL occur frequently in viral infections, particularly in HIV (49.75%), HBV (24%) and HCV (20%), it is very rarely associated with anti-beta2 glycoprotein I antibodies (anti-beta2GPI) and is not correlated with thrombosis risk or hematological manifestations of the antiphospholipid syndrome (APS). Concerning bacterial infections, aCL is often present in leprosy (42.7%), where it is frequently associated with the presence of anti-beta2GPI (44.8%), and in syphilis infections (8 to 67%), though without correlation with thrombotic events. Though few individual patients with unequivocal infection-induced aPL satisfy criteria for APS, the lack of statistical association with thrombotic events strongly argues against the identification of a true APS subset in this context. However, physicians should keep in mind the fact that an infection, generally bacterial, in patients with confirmed APS, may lead to catastrophic antiphospholipid syndrome with a possible fatal outcome.

Towards a strategy of universally efficacious vaccination against pathogens uniquely susceptible to cell-mediated attack.

Infection by some intracellular parasites is contained only by cell-mediated immunity, and yet antibody is produced at the expense of the cell-mediated response upon natural infection, leading to chronic or fatal disease. Effective vaccination must therefore generate an immunological imprint ensuring a strong and stable cell-mediated response upon infection. Such diseases include leprosy, tuberculosis, the leishmaniasis and AIDS (Kaplan and Cohn (1986) Int. Rev. Exp. Pathol. 28, 45-78; Surcel et al. (1994) Immunology 81, 171-176; Pearson et al. (1983) Rev. Infect. Dis. 5, 907-927; Clerici and Shearer (1993) Immunol. Today 14, 107-111). BALB/C mice are susceptible to Leishmania major, a protozoan that causes cutaneous leishmaniasis in man, by the criterion that substantial infection results in antibody production and progressive disease (Locksley and Scott (1991) Immunoparasitology Today, A58-A61; J.N. Menon and P.A. Bretscher, unpublished data). Infection of BALB/C mice with very few parasites results in an exclusive cell-mediated, Th1-like response and resistance to an ordinarily pathogenic, high dose challenge. This resistance is associated with a strong and stable cell-mediated response (Bretscher et al. (1992) Science 257, 539-542; J.N. Menon and P.A. Bretscher, unpublished data). The generation of this Th1 imprint by low dose infection has been achieved with three very different strains of the parasite. There is a similar dependency of susceptibility and resistance on relative parasite dose in 'susceptible' and 'resistant' mice and in mice of 'intermediate susceptibility'. For example, 'resistant' mice are resistant to substantial infection but succumb to infection with very high doses of parasites. We therefore propose that infection of a genetically diverse population with a very low dose of viable parasites, that does not induce antibody in any individual, will either induce cell-mediated immunity and contain the parasite, or the parasite will grow until it reaches the threshold required to induce cell-mediated immunity, thereby generating the required imprint. Low dose infection may thus constitute universally efficacious vaccination. The pertinence of these observations to improving the efficacy of BCG vaccination against tuberculosis is discussed.

An hypothesis to explain why cell-mediated immunity alone can contain infections by certain intracellular parasites and how immune class regulation of the response against such parasites can be subverted.

Cells with a low density of parasite-specific antigens on their surface are postulated to be susceptible to a cell-mediated attack but not to effector mechanisms normally activated following the binding of specific antibody to the infected cell. It is further postulated that such infected cells normally induce a cell-mediated response, and that cells infected with slow-growing intracellular parasites have a low density of parasite-specific antigens on their surface. Despite these general postulates, cell-mediated immunity is not invariably induced following natural infection by certain slow-growing parasites, such as those responsible for leprosy, tuberculosis, and the leishmaniases, and antibody can be induced that is exclusive of a strong, cell-mediated response. It is proposed that certain events in such cases subvert the normal regulatory processes that control the class of immunity induced. In these cases, the parasite-infected cells, bearing a low representation of parasite antigens, induce antibody even though they are not susceptible to antibody-dependent effector mechanisms, and so they are not eliminated. In this case, chronic infection and uncontrolled growth of the parasite occurs, often with fatal consequences.

Rheumatoid factors in leprosy and parasitic diseases.

Rheumatoid factors (RFs) occur with higher frequency and in higher titres in multibacillary forms of leprosy and several parasitic diseases than in healthy controls. The selection of controls is essential in studies of this kind. They should be individuals without signs of the disease under study living under similar socioeconomic conditions as the patients in the endemic country. In three studies where this matter was considered, RFs in lepromatous leprosy and Chagas' disease reacted more strongly with rabbit than human IgG, a feature generally considered to be quite restricted to rheumatoid arthritis. RFs interfere in various test systems, particularly in inducing false positive reactions for specific IgM antibodies in parasitic and other infectious diseases. Model experiments in rats, in vitro culture studies, and observations in humans indicate that RFs may have a protective role in trypanosome infections, malaria and schistosomiasis respectively.

Antibodies to tubulin in patients with parasitic infections.

Sera from a total of 268 patients with protozoan, helminth, bacterial (leprosy and tuberculosis) infections or appropriate controls, were assayed for anti-tubulin antibodies in an indirect enzyme-linked immunosorbent assay (ELISA), using purified tubulin as antigen. Levels of serum anti-tubulin antibody were significantly elevated in 67% of patients with visceral leishmaniasis, in 60% of patients with cutaneous leishmaniasis, in 89% of patients with onchocerciasis, in 100% of patients with schistosomiasis, and in 94% of patients with leprosy. Little or no increase in anti-tubulin antibody levels was seen in sera from patients with malaria (Plasmodium vivax) or tuberculosis.

Immunopathology of parasitic diseases: a conceptual approach.

These studies would indicate tremendous variations in the clinical manifestations of parasitic disease, resulting from characteristics of the parasite, the host, and their interaction. They further suggest that the conceptual mechanistic model described in the introduction is highly applicable. Previous evidence to substantiate the validity of such a model in schistosomiasis, a variety of protozoan diseases, and leprosy has already been presented (Phillips and Fox, 1982). This report would appear to lend additional credence to the postulates and suggests that upon scrutiny, the model represents a reasonable explanation for a wide variety of clinical manifestations of a parasitic disease. In addition, it may provide a working hypothesis for the interpretation of the immunopathology found in other diseases such as filariasis. Figure 3 compares and contrasts schistosomiasis and filariasis within the context of this hypothesis. Immunopathology results from the relative balance of host-parasite immunogenic factors and modulatory specific and nonspecific factors. The resultant immunopathology results from a number of immunologic mechanisms, but for the sake of comparison can be placed in certain analogous groups. Clearly, although a number of experimental questions still exist, vis-à-vis these analogies, it would appear that they are reasonable comparisons. It is hoped that such a conceptual approach might provide a useful framework for an understanding of the spectrum of immunopathology resulting from parasitic disease. These concepts might possibly lead to the eventual control of immunopathology.

Soluble immune complexes in human disease.

The great variety in biochemical properties of immune complexes occurring in human and animal disease states has made the detection of such complexes a difficult task. Variability in immune complex size, specificity, and interaction with humoral or cellular receptor systems, such as complement and phagocytes, suggests different pathogenic properties. The introduction of radioimmunoassays and the recently improved knowledge of the immune complex-receptor interactions have lead to the description of a large number of detection procedures, which in turn has widened the catalogue of diseases associated with immune complexes. This widespread occurrence of soluble immune complexes has lead many investigators to think that such complexes may occur either as a transient physiological phenomenon, important for fast clearance of the antigen, or as primary pathogenic factors triggering inflammatory reactions. Among the 50 procedures for immune complex detection known today, the article will select some pertinent tests, which will be discussed with respect to their specificity, sensitivity, and reproducibility. Furthermore, it is well known that when applied to the study of a patient group with one particular immune complex disease, various tests will result in different percentages of patients having complexes. This observation is due to differences in the underlying principle on which the various tests are based. Thus immune complexes must be further characterized with respect to their size, to the antibody class or specificity involved and, most difficult, to the antigenic specificity which participates in the complex. Recent advances in such experimental characterization of immune complexes in vitro and in the clinical evaluation of patients with complement activation associated to the presence of immune complexes will be discussed.