A propos time and autoimmunity.

The integrated defense system has been shaped over eons showing noteworthy robustness by surviving a million-year prehistory, a comparatively short evolving history and current transformation. Self-identification being part of it, so are deviations manifold expressed in autoimmunity. Epidemiological incidence and intensity, both being subject of change, are focused in the light of the time factor. Furthermore, it is stressed that there is no bi-univocal mutual relationship between immunity and defense and the origins of autoimmunity still remain mysterious. We question whether the present transforming events have occurred within too short a time to be attributed to genetic predisposition exclusively.

Asymmetry alters immune-partner relationship.

Ambiguity in the mutual manipulation between the immune system, more appropriately termed integrated defense system, on the one hand and microbes and incipient tumors on the other, is to be taken into account. Such ambiguity may also apply to autoimmune infighting. Here we consider the association of its increased incidence with modern ways of living. Indifference about fate implies that longstanding, evolutionary regulated, immune/tissue relationships are no impediment for asymmetric estrangement promoted by ongoing globalization.

Fibrosis regression induced by intravenous gammaglobulin treatment.

OBJECTIVES: To review case histories of patients in whom fibrosis played a significant role in the pathogenesis of their disease, and to determine whether intravenous gammaglobulin (IVIg) contributed to the regression of their fibrotic condition. METHODS: Eight patients with excess fibrotic reaction in the course of diverse diseases were analysed; a tendency that reverted with different IVIg treatment options. Myelofibrosis was predominant in three patients (a patient with a myeloproliferative syndrome, one with systemic lupus erythematosus, and one with Sjögren's syndrome). Three patients had scleroderma as their main feature, one patient had hepatitis C cirrhosis, and one had idiopathic thrombocytopenic purpura. RESULTS: Fibrotic excess was reduced in all the patients by IVIg treatment. In five patients the disease as a whole benefited from the infusion of immunoglobulins. CONCLUSION: IVIg may enhance resorption of fibrosis and promote healing in patients with fibrotic associated disorders.

High dose intravenous immunoglobulin repertoire versus anti-D. Disproportions in quantity and quality.

Here we consider certain therapeutic effects that intravenous administration of pooled high dose immunoglobulin and anti-D IgG share. Despite million-fold difference in doses such an effect occurs at least in idiopathic thrombocytopenic purpura (ITP). We postulate that spontaneous bleeding events may remit even when platelet numbers show refractoriness. We also mention the possible sparing of anti-D antibody-coated red blood cell (RBC) destruction and, finally, an acceleration of fibrotic involution. Fc receptors (FcRs) play a central role; beyond the well-established interactions with the immunoglobulin Fc fragment, FcRs are supposed to display special cognitive properties that enable them to pick out the therapeutic molecules from the recipient's IgG pool. Such subtle selection suggests some disarray in the host. On the other hand it may explain why the often-encouraging outcome of IVIG therapy remains unpredictable.

IVIG-pools: regulatory gifts--transiting from harmony toward harmonious immunoglobulins: why? and why not?

Based on 'initial conditions' which depend on each donors' exposure to a unique environment, a pooled intravenous immunoglobulin (IVIG) product transfers its immunoglobulin molecule repertoire, unchanged, to the altered host. The relay function of the cell-bound receptors, especially that of the inhibitory Fc(gamma)RIIB, may then allow sufficient amplification to make regulatory activity possible. To the clinician, IVIG may be considered a tool to promote reversal of the dysregulation causing autoimmune disease. Generically, IVIG may be seen as a promoter allowing a progression from harm by an inflammatory/fibrotic reaction, then down-regulating toward restitutio ad integrum. By modifying natural processes, IVIG may play minor roles in promoting defense against spontaneous bleeding and, perhaps, stimulating remyelination. The wide spectrum of IVIG specificities, by reflecting evolutionary epitope selection, may not further destabilize cell/molecule disarray in the affected host. Benefit to the patient by IVIG treatment cannot be predicted nor can potentially severe or even fatal accidents entirely be excluded. Important aspects of IVIG treatment still await clarification including dosage, timing and the isotype form. In the foreseeable future it does not seem that biotechnological advances will match the physiologic harmony of IVIG, leaving antibody characteristics aside.

Defense system shortcuts and limits of scope.

Defense, as a key factor of life, shares the biological tendencies of simplicity and energy saving. We propose that, like the mind, defense tends to rely on shortcuts via immune memes. Also, response repetition may induce the formation of virtual 'modules' [toolkits] to simplify and perfect performance. Engaged modules may expand by proliferating or by capturing immune components from the 'dormant' and even perhaps from active ones. With regard to recovery and/or survival, complexity of the integrated defense system (IDS) (1) requires to be inside of what we call the 'functional window'. In contrast to the physiological and common disease repair, energy is squandered when IDS perceives real danger. Our concern is the uncertain transition to conditions that do not fit into the IDS routine and, even worse, that are outside the functional window where the system is lacking.

No man is an island; no island is an island: does the immune network extend beyond the limits of skin?

Now that we are moving towards a post-antibiotic era, it may be necessary to reevaluate our concept of immunology. A long-standing handicap may be that, thus far, we have focused exclusively on the individual and his own immune machinery. A search for community interactions, also involving microflora, may provide clues for our survival under the extremely unhygienic conditions of the past as well as the present. Among the many adverse factors, could there also be hidden beneficial effects as well? If so, the development of such factors to therapeutic significance would be a worthwhile challenge. Diverse historical chronicles and a certain resistance shown by infants in shanty towns, after the maternal immune protection has faded and until their own immune system is fully developed, led us to postulate that adaptation is a prerequisite for any subject in order to benefit from unhygienic crowded conditions.

Combining IgG and interferon alpha-2b in chronic hepatitis C virus infection.

Treatment of chronic active hepatitis C virus (HCV) liver disease remains unsatisfactory. Interferon alpha 2b (IFN) has shown favorable though often unsustained effects. Besides its antiviral properties, IFN is a recognized immune modulator. We present data showing the favorable evolution of a case treated with IFN and IgG. Besides the antibody repertoire, the influence of IgG on the immune network is increasingly considered. The complex interactions resulting from combining drugs with immunomodulatory properties, such as IFN and different IgG preparations, may sound confusing. However, it might provide an insight into the outcome of chronic HCV infection, in which, evidently, immune components are heavily implicated. Prolonged treatment, with high-dose intravenous immunoglobulin (IVIG) seemed to be effective, either independently or by potentiating IFN.

Are there options for donor-derived i.m. anti-D IgG preparations other than to prevent Rh(D) sensitization? The intravenous route.

The use of i.v. anti-Rh(D) IgG for conditions other than prevention of Rh(D) sensitization is discussed. Besides highlighting the platelet response in ATP, a putative distinctive effect on the hemorrhagic threshold is suggested. Accordingly, we have included discussion of cases of aplastic anemia, myelodysplasia, heavy chemotherapy, coagulation deficiency, and senile vascular atrophy. We have also considered attempts to replace the high-dose pooled i.v. IgG (IVIG) with the much smaller amounts of IgG present in anti-Rh(D) preparations used to prevent Rh-sensitization in pregnancy. Both Fc and variable fragments of the IgG molecule may play a role, the former potentiated by manufacture-induced IgG aggregation and the latter by donor hypersensitization. A role for IgG-anti-F(ab')2 molecules cannot be ruled out.

A vascular effect of IgG therapy may prevent transplacental red cell leakage and spontaneous thrombocytopenic haemorrhages.

It is postulated that intravenous immunoglobin therapy may improve the red cell barrier of placenta and of capillary endothelia; the former protecting against anti-Rh antibody booster reaction and the latter preventing spontaneous thrombocytopenic bleedings. The effect on permeability may also reduce the passage of anti-Rh antibodies to the foetus.