Search

Background: The hygiene hypothesis proposes that reduced exposure to infectious agents in early life would explain the increase of allergic and autoimmune diseases observed over the past decades in high-income countries. Methods: We conducted a matched case-control study on incident atopic dermatitis (AD). Cases were 426 outpatient children with a first diagnosis ofincident AD. Controls were 426 children attending a pediatric/dermatological visit for nonatopic disorders matched to cases (1:1). Particular attention was paid to the time elapsed between the markers of microbial exposure and disease onset, and we considered for controls the same time window of exposures from birth as his/her matched case. Odds ratios (ORs) were computed using multivariable conditional logistic regression models, according to center, sex, age, and period of enrollment, and including as potential confounders a family history of any allergy in parents, type of delivery, having siblings, keeping pets, age at weaning, and having had ≥4 infections. Results: The OR of AD first occurrence was 0.35 (P-value=.039) for children who had experienced ≥4 infections compared with those with no infections. A decreasing trend in risk was observed with increasing number of siblings (P-value=.023), the protective effect reaching about 40% for children with 2 or more siblings (OR=0.62; P-value=.048). Pet keeping, in particular daily contact with dogs, was inversely associated with AD risk (OR=0.40; P-value=.004). Conclusions: These results support the hygiene hypothesis in its broad sense. Early-life environmental exposures, including pathogens and commensals, act as “microbes contact carriers” influencing immune system balance early in life.

Summary Insulin-dependent (type 1) diabetes is a prototypic organ-specific autoimmune disease resulting from the selective destruction of insulin-secreting β cells within pancreatic islets of Langerhans by an immune-mediated inflammation involving autoreactive CD4+ and CD8+ T lymphocytes which infiltrate pancreatic islets. Current treatment is substitutive, i.e. chronic use of exogenous insulin which, in spite of significant advances, is still associated with major constraints (multiple daily injections, risks of hypoglycaemia) and lack of effectiveness over the long term in preventing severe degenerative complications. Finding a cure for autoimmune diabetes by establishing effective immune-based therapies is a real medical health challenge, as the disease incidence increases steadily in industrialized countries. As the disease affects mainly children and young adults, any candidate immune therapy must therefore be safe and avoid a sustained depression of immune responses with the attendant problems of recurrent infection and drug toxicity. Thus, inducing or restoring immune tolerance to target autoantigens, controlling the pathogenic response while preserving the host reactivity to exogenous/unrelated antigens, appears to be the ideal approach. Our objective is to review the major progress accomplished over the last 20 years towards that aim. In addition, we would like to present another interesting possibility to access new preventive strategies based on the ‘hygiene hypothesis’, which proposes a causal link between the increasing incidence of autoimmune diseases, including diabetes, and the decrease of the infectious burden. The underlying rationale is to identify microbial-derived compounds mediating the protective activity of infections which could be developed therapeutically.

Conflicting results have been reported concerning the effect of adult thymectomy (A-Tx) on the mixed lymphocyte reaction (MLR) response. Our purpose was to test the reverse question, namely the effect of A-Tx on the stimulatory capacity of mouse lymphocytes carrying allelic disparities at the Mls and the H-2 loci. Spleen cells from A-Tx CBA donors were found to be significantly more stimulating than cells from normal donors. That A-Tx could eliminate suppressor T cells involved in MLR regulation or in preventing back stimulation is not likely according to our data. An increment in expression or in accessibility of Mls or H-2 antigenic determinants induced by A-Tx is no more likely, since a smilar increase in lymphocyte proliferation was observed in syngeneic cultures. The most probable explanation remains that A-Tx discloses a strongly stimulatory subpopulation, perhaps acting in part nonspecifically. The hypothesis of an enrichment in B cells versus a loss of T cells is not compatible with our findings, since B-cell-enriched fractions from various origins never attained the stimulating ability disclosed by A-Tx cells. Moreover, the cell involved is theta-positive, although slightly nylon-wool-adherent, and thus shares several properties with immature T cells involved in auto-rosette formation.

By using polyethylene glycol precipitation at low concentration (PEG test) and the radiolabeled Clq binding test, immune complexes were detected in sera from acute (23/28) and chronic (28/32) hepatitis patients, hemodialyzed patients with chronic hepatitis B surface (HBs) antigenemia (7/19), and asymptomatic HBs antigen carriers (2/11). After treatment of PEG precipitates with acidic pH, heating, or proteolytic enzyme (protease), electroimmunodiffusion or radioimmunoassay revealed the presence of HBs antigen or antibody in dissociated immune complexes in sera from several acute and chronic hepatitis patients. Electron microscopy showed immune complexes of HB virus in 9 of 12 PUG precipitates obtained from PEG-test-positive sera; these 9 precipitates were from patients with acute or chronic hepatitis and the other three from chronic HBs Ag carriers. Free HB virus particles were observed after protease digestion of PEG precipitates. Neither immune complexes nor virus particles were seen in precipitates from PEG-test-negative but HBs-Ag-positive sera from chronic carriers.

Resume Moins de dix ans apres la decouverte des hybridomes par Kohler et Milstein en 1975, le premier anticorps monoclonal etait injecte chez l’Homme pour prevenir le rejet des greffes. Il s’agissait d’un anticorps dirige contre la molecule CD3 qui intervient dans la transduction du signal aux cellules T apres la reconnaissance de l’antigene. Paradoxalement, en raison d’hesitations pharmaceutiques retrospectivement injustifiees, la classe therapeutique se developpa lentement. Il fallut attendre les annees 1990 pour voir emerger d’autres specificites. Parallelement, on avait appris a modifier les anticorps par genie genetique pour les humaniser en changeant la majorite des determinants d’espece de la souris qui les avait produits par des determinants humains. Il se revela meme possible de produire des anticorps totalement humains selon plusieurs strategies faisant appel a des souris transgeniques ou chimeriques (homme/souris) ou meme a des productions totalement in vitro (phage display ). Ce fut alors une efflorescence de nouveaux anticorps utilises dans des indications tres variees : toujours la transplantation d’organes (anti-CD2, anti-CD4, anti-CD25, anti-CD40L), mais egalement la pathologie infectieuse (anti-respiratory syncytial virus : RSV), les cancers (anticorps anti-CD20 et anticorps diriges contre les antigenes de tumeur) et les maladies auto-immunes (avec le grand success des anticorps anti-TNF). Il s’avere en fait que les anticorps monoclonaux representent une voie d’approche exceptionnellement efficace dans des domaines ou les produits chimiques conventionnels rencontrent des limites difficilement surmontables. Cette action particuliere des anticorps monoclonaux tient, a la fois, a leur specificite tres fine pour leurs cibles (qui peuvent etre variees a l’infini), mais aussi a leur capacite de donner des signaux positifs a des cellules dont notamles fonctions ne sont souvent qu’inhibees par les petites molecules. Une illustration de ce mode d’action est l’effetrecemment demontre par notre equipe de la restauration de la tolerance au soi par un anticorps anti-CD3 chez des sujets recemment devenus diabetiques et chez qui une remission tres durable de la maladie fut induite apres un traitement de seulement une semaine.

The Th1/Th2 concept brought an attractive explanation of the active self tolerance which appears to control the onset of pathogenic autoimmunity. New data coming from various independent horizons indicate that self immunoregulation could also depend to a large extent on non-Th2 cells. Original data derived from the day-3-thymectomy model, selective T-cell lymphocytopenia and nonobese diabetic mice are discussed in an effort to analyze similarities and differences in phenotype (CD25, CD62L and CD45RB) and cytokine pattern (notably interleukin (IL)-4, IL-10 and transforming growth factor (TGF)beta) of regulatory cells involved in these models. The relationship of these cells with Th3, Tr1 and natural killer (NK) T cells are also discussed. The hypothesis is proposed that CD25 CD62L T cells mediate the physiologic regulation of self regulation whereas Th2 and Th3 cells are essentially induced following sensitization against autoantigens.

Low doses of the CD3 mAb 145 2C11 restored self tolerance to beta cell Ags in adult overtly diabetic NOD mice. Within 2 to 4 wk after treatment, complete and permanent remission of diabetes was observed. Autoreactive T cells were not deleted in CD3 Ab-protected animals as evidenced first, by the persistence of peripheral insulitis and, second, by the capacity of spleen cells from CD3 Ab-treated mice to transfer diabetes to adult irradiated syngeneic recipients. Moreover, the conferred tolerance was reproducibly reversed by a single injection of cyclophosphamide. For 5 to 7 wk after treatment, IFN-gamma production by stimulated spleen cells was significantly decreased in treated animals. One unique feature was that the CD3 Ab-induced tolerance ensued only from treatment of overtly diabetic NOD mice. Durable protection was exclusively observed when treating mice with recent onset disease (14-20 wk old). At variance with this finding, treatment of 4- and 8-wk-old mice was without effect, and complete but transient protection followed the treatment of 12-wk-old NOD mice. The tolerogenic properties of 145 2C11 did not depend on its mitogenic capacity, since nonmitogenic F(ab')2 fragments also appeared potent at inducing durable remission in overtly diabetic NOD, although nonmitogenic CD3 F(ab')2 fragments could mediate T cell signaling, as evidenced by cytokine gene transcription (IL-2, IFN-gamma, IL-4, and IL-10) assessed by PCR on splenocytes from treated mice. A concomitant cyclosporine treatment abrogated the CD3 mAb-induced protection, further pointing to the crucial role of T cell signaling in the effect observed.

Background Findings on pet exposure and the risk of atopic dermatitis (AD) in children are inconsistent. Objective With the aim to summarize the results of exposure to different pets on AD, we undertook a meta-analysis of epidemiologic studies on this issue. Methods In August 2012, we conducted a systematic literature search in Medline and Embase. We included analytic studies considering exposure to dogs, cats, other pets, or pets overall during pregnancy, infancy, and/or childhood, with AD assessment performed during infancy or childhood. We calculated summary relative risks and 95% CIs using both fixed- and random-effects models. We computed summary estimates across selected subgroups. Results Twenty-six publications from 21 birth cohort studies were used in the meta-analyses. The pooled relative risks of AD for exposure versus no exposure were 0.72 (95% CI, 0.61-0.85; I 2 = 46%; results based on 15 studies) for exposure to dogs, 0.94 (95% CI, 0.76-1.16; I 2 = 54%; results based on 13 studies) for exposure to cats, and 0.75 (95% CI, 0.67-0.85; I 2 = 54%; results based on 11 studies) for exposure to pets overall. No heterogeneity emerged across the subgroups examined, except for geographic area. Conclusion This meta-analysis reported a favorable effect of exposure to dogs and pets on the risk of AD in infants or children, whereas no association emerged with exposure to cats.

A quantitative trait locus for increased IgG serum levels in the NOD mouse strain was mapped to distal chromosome 1, close to the fcgr2 locus encoding the low-affinity type II receptor for the Fc portion of IgG (Fc gamma RII). Expression of membrane-inserted (b2) and soluble (b3) isoforms of Fc gamma RII was strongly decreased in macrophages of NOD compared with C57BL/6 (B6) mice. In contrast, B cell-specific (Fc gamma RIIb1) isoform was only slightly decreased and Fc gamma RIII was not altered. This Fc gamma RII regulatory defect was cis-encoded by fcgr2 or by a closely linked locus, occurred at the mRNA level, and was associated with multiple mutations in the fcgr2 gene promoter. In relation with this defect, binding of IgG1- and IgG2b- but not IgG2a-opsonized RBC by macrophages of NOD and congenic B6.NOD-fcgr2 mice was severely impaired, but was normal in macrophages of NOD.B6-fcgr2 congenic mice, indicating that Fc gamma RII plays a nondispensable role in binding of IgG1 and IgG2b isotypes. Likewise, serum levels of IgG1 and IgG2b but not IgG2a were up-regulated in NOD compared with NOD.B6-fcgr2 congenic mice. These findings indicate that macrophage Fc gamma RII may regulate serum IgG1 and IgG2b through their catabolism, and validate the NOD strain as a model to investigate the functions of Fc gamma RII isoforms.

CXCL10, a gamma-interferon-induced chemokine seems to play a relevant role in lung involvement that occurs in systemic sclerosis (SSc). The objective of this study was to assess the serum level of CXCL10 in interstitial lung disease (ILD) associated with SSc.Serum level of CXCL10 was assayed in 23 healthy volunteers (60.0 years; 58.0-67.3) and 29 SSc patients (63.1 years; 60.1-69.4) by ELISA method. Pulmonary function tests (PFTs), lung CT-scan and echocardiogram were also performed in the patients. Serum levels from patients and healthy controls were compared and a comparison among SSc patients between those with and without ILD, as documented by lung CT-scan, was also performed.Median CXCL10 level from patients with SSc was significantly higher than that from healthy volunteers (110.0 pg/ml; 60.8-223.8 versus 52.0; 41.3-65.8; p0.001). Fifteen out of the 29 patients had ILD on lung CT-scan; the median CXCL10 level from SSc patients with ILD was significantly higher than that from SSc patients without ILD (210.0 pg/ml; 115.0-307.5 versus 76.0; 55.0-110.0; p=0.02).Our findings suggest that CXCL10 is specifically increased in the lung involvement of SSc and plays a role in scleroderma lung disease.

Thymic epithelial cells (TECs), the major component of the thymic microenvironment, can be modulated by pituitary hormones. We have shown previously that prolactin (PRL) can influence the endocrine activity of TECs and stimulate TEC proliferation as well as cytokeratin expression, suggesting the existence of PRL receptors on TECs. Using a series of monoclonal antibodies (mAbs) to the extracellular domain of the rat liver PRL receptor, we have demonstrate that rat TECs bear specific receptors for PRL, as assessed by immunoblotting as well as by immunocytochemistry experiments. Using a probe specific for the long form of PRL receptor, mRNAs of 6.7 and 10.1 kilobases were detected, although by immunoblot the major protein in TECs had a molecular mass of 43 kDa. Functionally, these mAbs were able to modulate thymulin secretion, as well as TEC proliferation. Moreover, the mAbs cross-reacted with human TECs and were able to mimic the action of PRL on these cells. These data bring further support for the general concept of the neuroendocrine immune circuit and extend the notion for a pleiotropic role of PRL as an immunomodulatory hormone.

The adoptive transfer of type I diabetes in nonobese diabetic mice requires the contribution of both CD4+ and CD8+ T cells. To further elucidate the cellular pathway(s) of beta-cell destruction and the responsibility of each subset, high doses of committed T cells from diabetic mice purified to single subsets, were injected into syngeneic nonobese diabetic neonates. The recipients of single or mixed subsets were followed for clinical manifestations of diabetes and examined at 30 days of age for in situ lesions. None of the animals injected with either CD4+ or CD8+ T cells became overtly diabetic during the 30 days of observation whereas 8 of 23 mice inoculated with a mixture of the two subsets developed glycosuria and hyperglycemia. However, insulitis was found in 6 of the 13 mice injected with CD4+ T cells whereas only 1 of the 9 mice injected with CD8+ T cells showed marginal infiltration of the pancreas. The lesions initiated by CD4+ T cells alone were considerably less severe than those induced by the mixture of both subsets, corroborating the fact that overt disease did not occur in the former group. Together, these results suggest a distinct function for each diabetogenic T cell subset. CD4+ T cells, which have the capacity to home to the pancreas, promote in turn the influx of CD8+ effector T cells that do not by themselves accumulate in this organ. These results illustrate a novel form of T-T cell interactions leading to organ specific autoimmune lesions.

The presence of histamine H1 receptors on lymphocytes has been indirectly suggested by the various effects of agonists or antagonists on the functionally distinct T lymphocyte subsets. Recently, a new H1 antagonist, 125I-iodobolpyramine, whose structure is similar to mepyramine, has become available for the detection of H1 receptors in guinea pig brain. When using 125I-iodobolpyramine on human T lymphocytes, the presence of a single highly specific H1 binding site was evidenced. The binding of 125I-iodobolpyramine to human T cells was reversible when using 1000-fold excess of the cold H1 antagonist, d-chlorpheniramine. Binding saturation was achieved at 0.60-0.65 nM of 125I-iodobolpyramine, the binding equilibrium was reached in 20-30 min at 27 degrees C. The dissociation constant was KD = 0.41 +/- 0.07 (mean +/- SE) and the number of receptors per T cell was 3407 +/- 592 (mean +/- SE) as deduced from saturation and kinetic curves. In competition experiments using a panel of H1 ligands, the T cell binding sites detected by 125I-iodobolpyramine showed a pharmacological behavior characteristic of histamine H1 receptors. It was of particular interest that 125I-iodobolpyramine binding displayed clearcut stereoselectivity as assessed by the higher affinity of the d-configuration of chlorpheniramine than the l form. Study of purified CD4 and CD8 T cells showed that twice as much H1 histamine receptors were expressed by CD8 T lymphocytes (6615 +/- 1125) as compared to CD4 T cells (3545 +/- 459). These results underline the need for studying the functional properties of such pharmacologically defined T lymphocyte H1 binding sites.

Less than ten years after the discovery of hybridomas by Kohler and Milstein in 1975, the first monoclonal antibody was injected in humans to prevent graft rejection. The antibodies used were targeted against the CD3 molecule involved in the transduction of T cell signals after recognition of the antigen. Paradoxically, because of pharmaceutical hesitations later found to be unwarranted, the therapeutic class developed slowly. It was not until the 1990s that other formulations emerged. In parallel, work was undertaken to modify the antibodies using genetic engineering techniques to humanize the molecules by changing the majority of the species determinants from the murine producing animals to the human recipients. It was even found possible to produce totally human antibodies using several different strategies based on in vitro phage display. This led to rapid development of new antibodies used for a wide range of indications: organ transplantation (anti-CD2, anti-CD4, antiCD25, antiCD40L), as well as anti-respirator syncytial virus (RSV) for respiratory infections, and anti cancer agents (Anti-CD20 antibodies and anti-tumor antibodies), as well as autoimmune diseases (with significant success with anti-TNF antibodies). It was found the monoclonal antibodies offer an exceptionally effective method in domains where conventional compounds have reached their limit. This specific action of monoclonal antibodies, with fine specificity for the targets (which can be varied to infinity), as well as their capacity to provide positive signals to cells whose functions are not often inhibited by small molecules. An illustration of this mode of action is the effect recently demonstrated by our team on restored self tolerance using anti-CD3 antibodies in newly diagnosed diabetics in whom sustained remission can be injected after less than one week's treatment.

Insulin-dependent mellitus diabetes is an autoimmune disease resulting from the destruction of the beta cells of the islets of Langerhans by autoreactive T cells. Various approaches are being investigated in order to slow down the progression of diabetes using immunotherapy. The most promising results are based on the induction of specific tolerance following the administration of soluble autoantigens or monoclonal anti-CD3 antibodies. These strategies, initially developed in the NOD mouse, have been proven to be efficacious in recently diagnosed diabetics.

Autoimmunity is physiological: in every normal individual autoreactive T cells and B cells which produce natural autoantibodies, exist. Auto-immunity becomes pathological, giving rise to an autoimmune disease, when the number of autoreactive cells, and particularly the avidity of their receptors for autoantigens increase. Triggering of the disease depends both on the increase in immunogenicity of the target cell, which may be secondary to a viral infection, and the individual's own capability to recognize the antoantigens (HLA genes, T cell repertoire). More rarely, the disease is caused by an infectious agent leading to a crossed reaction with an autoantigen (Guillain-Barré syndrome). Nevertheless, all these elements are not sufficient to provoke a chronic disease such as multiple sclerosis or myasthenia gravis. The passage to chronicity is usually secondary to a defect in immunoregulation. Several categories of regulatory T cells have been found: Th2 cells, CD25+ cells, Trl cells, NKT cells. It is still difficult to asses the responsibility of the defect of one of these populations in a given disease, or to single out the cytokines implicated, although an essential role is often given to interleukin 10 and/or TGFB. Even if the pathogenic autoimmune reaction is triggered by the autoantigens of the target cell, there is apparently not a unique autoantigen target. The specificity of the reaction spreads progressively from one antigen, which may vary among subjects, to the entire target cell. It is based on these notions that new immunotherapeutic approaches for autoimmune diseases are being developed (soluble autoantigens, or one of their modified peptides: (APL), cytokine, anti-CD3 antibody).

To investigate the putative involvement of poly(ADP-ribose) polymerase (PARP) alleles in systemic lupus erythematosus (SLE) and primary antiphospholipid syndrome (APS).This study of French Caucasians included 171 unrelated patients with SLE, 88 unrelated patients with primary APS, and 193 ethnically matched healthy controls. The SLE group comprised 89 patients with sporadic SLE and 82 patients with familial SLE. Patients' and controls' DNA were genotyped for the various alleles of a polymorphic CA dinucleotide repeat located within the promoter region of PARP.No statistically significant difference was observed for the distribution of PARP alleles between the healthy control group and each patient group or the pooled SLE patient group.The study findings strongly suggest that these alleles do not influence susceptibility to SLE or primary APS in French Caucasians.

The first administration of CD3 monoclonal antibodies, such as anti-human CD3 (OKT3), induces a massive release of several cytokines, including tumor necrosis factor alpha (TNF-alpha), interferon (IFN)-gamma, interleukin (IL)-2, IL-3, IL-6, and granulocyte-macrophage colony-stimulating factor.Cytokine levels in patient's sera were measured by specific ELISA. In vitro cultures were performed using OKT3-stimulated peripheral blood mononuclear cells and/or whole blood from patients and normal controls.Here we describe that OKT3 administration to human renal allograft recipients also leads to a significant release of IL-10. Contrasting with most OKT3-induced cytokines, such as TNF-alpha whose release is transient, IL-10 levels show a more progressive increase, they peak only by 4-8 hr after the first OKT3 injection and persist longer. Thus, significant IL-10 levels are still detectable at the time of the second and the third OKT3 injection. Administration of corticosteroids, 1 hr before the first OKT3 injection, significantly reduced both TNF-alpha and IL-10 release. Experiments were performed to evaluate the source(s) of IL-10 and its (their) influence on the initial T-cell activation. When stimulated in culture with soluble OKT3, the production of IL-10 was dependent on the cooperation between T lymphocytes and monocytes. It is important that, as assessed through the use of a specific neutralizing antibody, the endogenous IL-10 produced in the co-culture system exerted a negative feed-back on the release of the other pro-inflammatory CD3-induced cytokines, which was reproducible.These results are supportive of a major role of IL-10 in the down-modulation of the OKT3-triggered T-cell activation cascade.

Pathogenic autoreactive T lymphocytes are mediators of spontaneous insulin-dependent diabetes in nonobese diabetic (NOD) mice. This is demonstrated by their capacity to transfer diabetes into syngeneic immunoincompetent recipients. In addition, especially in prediabetic NOD mice, peripheral CD4+ T lymphocytes were identified that are highly effective, in conventional mixing cotransfer experiments, at preventing disease transfer. The present data demonstrate that mature heat-stable Ag-TCR alpha beta+CD8-thymocytes from prediabetic NOD mice also express this inhibitory capacity. Selection using an L-selectin (CD62L)-specific Ab showed that TCR alpha/beta+CD4+CD62L+ thymocytes, emerging from the mainstream differentiation pathway, concentrate this ability to regulate autoreactive effectors. Compared with mature TCR alpha beta+CD8- thymocytes, significantly lower numbers of TCR alpha beta+CD4+CD62L+ were sufficient to achieve an efficient inhibition of disease transfer into NOD-scid recipients. This protective ability was potentiated following in vitro culture in the presence of IL-7. In contrast, TCR alpha beta+CD62L- thymocytes, highly enriched in class I-restricted NK T cells, were unable to influence diabetes transfer. Identical results were obtained using thymocytes that have been cultured in vitro for 4 days in the presence of IL-7. These results support the active role in NOD mice of a thymus-derived CD4+ subset that controls peripheral pathogenic autoimmune effectors.

Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease with a predominantly non-hereditary etiology that results in a destruction of pancreatic beta cells by autoaggressive T lymphocytes. Neither the mechanism of initial stimulation of these T cells nor the nature of the environmental factors implicated in the disease have so far been identified. However, both issues are taken into account by the hypothesis of initial T cell activation by viral or bacterial mimicry peptides with sequence similarities to pancreatic self antigens. We determined sequential epitope motifs to search for mimicry peptides stimulating T cell lines specific for two epitopes derived from the IDDM autoantigen 65-kDa glutamic acid decarboxylase (GAD65). These were GAD65 (88-99), presented by HLA-DRB1*0101, and GAD65 (248-257), presented by HLA-DRB5*0101. T cell stimulation by peptides with substitutions in HLA anchor or T cell contact positions was analyzed to establish degenerate epitope motifs for database searching. Out of 28 tested candidate mimicry peptides derived from bacterial, viral and human proteins, 3 stimulated T cell lines and a T cell clone specific for epitope GAD65 (248-257). Our results demonstrate that mono- and polyclonal GAD65-specific T cells from IDDM patients can be stimulated by viral and bacterial peptides with little apparent sequence homology with autoantigenic epitopes. Moreover, in a synopsis with related published studies, our findings suggest that simple degenerate search motifs comprising principal T cell contacts plus HLA class II binding motifs may suffice to identify most mimicry peptides.

Open-angle glaucoma (POAG) is a highly prevalent cause of visual impairment. Six families grouping 71 living patients affected with juvenile-onset and middle-age POAG (age at diagnosis ranging from 10 to 65 years) were linked to the GLC1A locus. All patients carried a mutation of an evolutionarily conserved asparagine residue to a lysine at position 480 (N480K) in the olfactomedin-homology domain, which is encoded by the third exon of the GLC1A gene. The N480K mutation was also identified in 14 unaffected carriers who are at high risk of developing POAG. Although four of the families had ancestors identified in Northern France, the pedigrees could not be interconnected by genealogical investigation. However, haplotype analysis indicated that all the carriers had inherited the N480K mutation from the same founder. Screening of a selected set of 67 POAG patients who originated from Northern France and underwent trabeculectomy before the age of 50, detected one patient with the N480K mutation associated with the same disease haplotype already characterized in the 6 families. This group of 72 POAG patients is the largest one having a GLC1A mutation in common and provides a unique tool to investigate the factors influencing the variable expressivity of the GLC1A gene.

It was only in the late 1970s that the autoimmune origin of IDDM appeared as the most plausible hypothesis. The consistent finding of islet cell antibodies (ICA) [1] provided a firm basis for the existence of selective β cell directed autoimmune response. Approximately at the same time, in vitro evidence for cell-mediated immunity to islet cells was presented [2]. In the following years, two exceptionally informative spontaneous models of the disease, the bio breeding (BB) rat and the non-obese diabetic (NOD) mouse provided direct evidence for the role of autoimmunity. A considerable bulk of data has been collected since on the immunology and on the genetics of murine and human IDDM allowing a clear understanding of major aspects of the disease pathogenesis and to a lesser degree of its aetiology [3]. Many pending questions persist though. It is the aim of this chapter to review the main prevailing concepts of the immunology of IDDM and discuss the yet unsettled questions.

Predictive medicine is based on the early recognition of a pathologic process before the onset of clinical manifestations, followed by preventive therapy. Prediction can be achieved by identifying disease predisposing genes. However, this approach is usually insufficient because most often the disease is polygenic and the penetrance of genetic factors is incomplete, which reduces the reliability of the prediction. It is very useful when it is possible to complement this prediction by the study of biological markers allowing the detection of the triggering of the pathogenic process, before it has induced significant lesions or functional disturbances at the origin of clinical manifestations. Predictive medicine is only justified when it may lead to preventive therapy as in the exemplary case of juvenile glaucoma. The case of insulin dependent diabetes mellitus is also interesting, even if preventive therapy is not yet routinely available.

The functional capacity of the human monocyte receptor for the Fc portion of IgA (Fc alpha R) in mediating signal transduction was evaluated by cytokine release. F(ab')2 fragments of anti-Fc alpha R monoclonal antibodies (mAb) were used as specific probes to induce release of tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). Multivalent cross-linking by a secondary anti-mouse antibody [F(ab')2 fragments] induced a significant release of TNF-alpha and IL-6 by human blood mononuclear cells, indicating requirements for Fc alpha R aggregation on the cell surface to transmit signals. Both cytokines were released exclusively by adherent cells, identifying monocytes as the responding cells within the mononuclear cell population. This cytokine release could not be due to contaminating endotoxins, because it was not abolished by polymyxin B, a lipopolysaccharide (LPS) inhibitor. Moreover, purified recombinant soluble Fc alpha R inhibited the anti-Fc alpha R mAb-mediated cytokine release from blood monocytes, demonstrating that TNF-alpha and IL-6 were released in a receptor-specific manner. Our data suggest that Fc alpha R, through its capacity to mediate secretion of IL-6, may play an important role in B-cell proliferation and immunoglobulin production. On the other hand, release of TNF-alpha following stimulation of Fc alpha R molecules directly implicates these receptors in amplification and regulation of the inflammatory process occurring during IgA-mediated host defence.

Glutamate decarboxylase (GAD), especially the GAD 65 isoform, is a major autoantigen in autoimmune diabetes. To determine the role of GAD 65 in the pathogenesis of the disease, we developed a quantitative PCR method allowing to establish the absolute number of GAD 65 mRNA molecules expressed in pancreas of male and female non-obese diabetic (NOD) mice at 5 weeks of age, in comparison of the 2 non autoimmune mouse strains. It appeared that pancreatic expression of GAD was similar in the 3 strains (around 30,000 molecules/micrograms total RNA) in males. However, in the NOD mouse, sexual dimorphism was observed with low GAD 65 expression in the female known to show higher incidence of the disease than the male. This finding could contribute to the absence of GAD 65 tolerance in the female and suggests an hormonal control of GAD 65 gene expression.

The etiology of autoimmune diseases remains a matter of debate. The respective roles of predisposition genes and environmental factors on the one hand, and the opposing effect of promoting and protective factors, on the other hand, are still ill-defined. A large amount of data recently obtained in either experimental models or in human diseases open new perspectives in the understanding of this etiology. We shall briefly review here some of these data.