Slide 1

Dear Chairman, Dear Colleagues.

Slide 2

The immune system detects and eliminates pathogenesis discriminating self and non-self. The adaptive immunity is highly specific. The recognition of peptides as many as 10¹¹ by specific receptors on T and B cells allows the lymphocyte clonal expansion and T and B cell memory.

Slide 3

On the other hand innate immunity is quick and aspecific. It acts through the recognition of pathogen-associated molecular patterns, PAMPs by leukocytes but also by several other cells and this leads to opsonization and phagocytosis. But since it acts through the antigen processing the innate immunity is linked to the adaptive one. The exogenous ligands are recognised by serum or cell surface scavenger receptors, for instance polyanions, while carbohydrates which are carried by pathogens are recognised by selecting C-type lectins. But also endogenous ligands which are produced during stress and cell damage at heat shock proteins, EDA-fibronectin, biglycan, heparin sulphate, and several others are recognised by intracellular receptors. Pathogen products like LPS, peptidoglycan, glycolipids double or single strand RNA or viral bacteria but also endogenous ligands like  heat shock proteins and others are recognised by toll-like transmembrane receptors.

Slide 4

These receptors belong to 5 families and after the reaction with the specific ligands several adaptor molecules are recruited to the cytoplasmic tail of toll- like receptors. and MyD88 is the most common adaptor for all kinds of toll-like receptors except for toll-like receptor 3. Then protein kinases are joined and activated and this allows the nuclear translocation of several transcription factors. For instance, interferon reacting factor which leads to the release of interferon α and γ or the nuclear translocation of the two active subunits p50 and p65 of NF-kB.

Slide 5

Indeed the activation of NF-kB is the most relevant biological effect of toll-like receptor activation. The nuclear translocation with the 2 active subunits leads to the release of adhesion molecules, cytokines, procoagulants, vasoconstrictors which regulate innate/adaptive immune response.

Slide 6

The contact of microbial agents with immature dendritic cells leads to their maturation and so they induce innate immunity recruitment of macrophage and neutrophils on the site of infection. But those mature dendritic cells migrate to lymph nodes where they activate specific T lymphocytes and expand TH1 subclass by the effect of IL-12 but also TH2 lymphocytes under the effect of IL-10. Thus leading to the full expression of adaptive immunity.

Slide 7

So toll-like receptors not only discriminate pathogens from self and so are important for immune response against infections but they prime subsequent T cell response by activating the dendritic cell maturation, by upregulating MHC-II, by inducing co-stimulatory molecules, by secreting cytokines. So they are likely to be relevant not only for pathogen control but also for autoimmunity.

Slide 8

Indeed a couple of years ago it was shown that in a strain of SLE prone mice the injection of a specific TLR3 ligand was able to worsen the glomerular disease and a toll-like receptor 3 was observed in mesangial cells and infiltrating macrophages. The same was observed when the injection of ligands specific for TLR-7 or TLR-9 was performed. In the last issue of JASN it was reported that TLR-9 or TLR-7 inhibition prevent glomerulonephritis in experimental SLE.

Slide 9

Toll-like receptor 2 agonists exacerbate accelerated nephrotoxic nephritis. In an immune model of crescentic glomerulonephritis the injection with synthetic toll-like receptor 2 ligands which mimic the bacterial LPS induce a worsening of the nephritis. So toll-like receptor ligation can modify adaptive immune response.

Slide 10

Innate immunity plays a major role on the mucosa, this is well known. This is a 400 m2 interface with the environment.

Slide 11

Since its identification,  the relationship between IgA nephropathy and mucosal infections became relevant. The first hypothesis was indeed that environmental antigen exposure of mucosal antigen leads to increased synthesis of IgA thus the formation of IgA immune complexes, the accumulation of IgA immune complexes in the mesangial area and so the full development of IgA nephropathy and hematuria.

Slide 12

Since 20 years ago a mucosal origin of the IgA deposits in the mesangium was suggested. From an experimental point of view the hypothesis was confirmed by models of oral immunization, IgA reacting with environmental antigens in sera and in glomeruli of patients with IgAN  and the observation that tonsillar IgA reacted with the mesangial deposits. However, further investigations cast doubts about this hypothesis of mucosal origin of IgA deposits in the mesangium. It was rather suggested that this IgA originated from the bone marrow since there was an excessive production of dimeric IgA 1 in bone marrow in IgAN as demonstrated by John Feehally and an impaired IgA1 synthesis versus oral active immunogens in IgAN as reported by the Moh Daha group.

Slide 13

So, the criticism about the hypothesis of dysregulated mucosal immune response diverted the scientific interest towards another hypothesis that the deposition of IgA in IgAN was due to an aberrant glycosylation of serum IgA1. Indeed as you know there is a defective galactosylation or sialyation of O-linked glycans as was reported by several authors including ourselves.

Slide 14

However, there are interesting recent data. Indeed an abnormal systemic response was found in patients with IgAN to mucosally encountered antigens as recently reported by Feehally group. The pathogenetic role for secretory IgA in IgAN has been recently reported by the Daha group. The same group reported a mucosal origin of pIgA which is deposed in the mesangium of these patients and the fact that this IgA having N-linked glycosylation defects can activate innate immunity by a mannose-binding lectin complement pathway and I’m sure that M. Daha will refer on this topic later.

Slide 15

So, in the pathogenesis of IgAN there is a recent reconsideration of the role of innate immunity.

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Indeed, if we consider the experimental models of IgAN, the injection of macromolecular IgA as well as the oral immunization reproduces IgA mesangial deposits but without hematuria which is the most typical feature.

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However, in another experimental model produced by Steven Emancipator’s group by repetitive intranasal immunisation of Sendai virus followed by systemic challenge it was observed that not only the glomeruli contain mesangial deposits of IgA but hematuria and proteinuria developed.

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More recently Sandro Amore in collaboration with Steven Emancipator reported an expansion of this study over a long time immunisation of mice with Sendai virus either inactivated or intranasal immunisation with infectious virus and then with a challenge IV with infectious virus.

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They observed that in mice treated for 6 weeks, as well as in mice treated with infectious Sendai virus for 14 weeks, there was a strong deposition of IgG and IgA. While when the mice were exposed to protracted exposure of inactivated Sendai virus, there was a reduced level of IgA and reduced tolerance and in the mean time increased IgG deposits and hematuria.

Slide 20

So the hypothesis is that there is a potential contribution to IgAN development by virally induced innate responses in presence of defective mucosal immunity. The lack of mucosal tolerance may play a role in the development of IgAN.

Slide 21

The role of an infection has also been stressed also by other authors. The Japanese Koyama group reported that staphylococcus aureus cell membrane antigen is deposited in the mesangium of patients with post-MRSA infection. This antigen was found in more than 50% of patients with IgAN and they reported also that in an experimental model an induction IgAN in mice by staphylococcus aureus antigens.

Slide 22

So in conclusion our observation with Sendai respiratory virus experimental model the our recent data increased TLR-4 expression and NF-kB activation and switched from proteasome to immunoproteasome in the peripheral blood mononuclear cells of patients with IgAN supporting the activation of innate immunity in this disease.

Slide 23

Thank you.