Anticorps anti-CR1

La présence d’anticorps anti-CR1 a également été décrite chez des patients lupiques. Des études montrent que ces anticorps diminueraient l’expression de CR1 à la surface des érythrocytes (145,146) et perturberaient ainsi la prise en charge et l’élimination des CIC (147). Les éventuelles associations cliniques dans la maladie lupique restent à déterminer et rien a été décrit concernant son association à l’atteinte rénale, cependant, compte-tenu de l’implication de CR1 dans la physiopathologie de la NL, ces anticorps pourraient y jouer un rôle.

La figure suivante synthétise les grandes étapes qui permettraient le développement de la NL. Elle permettra de récapituler les différents éléments du complément qui seraient impliqués dans la physiopathologie de l’atteinte rénale lupique (figure 8).

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Figure 8 : Physiopathologie de la néphropathie lupique et implications du complément (96) Autoimmune Diseases 3 Glomerulus 1 2 3 4 5 6 7 8 9 10 Predisposing factors Apoptotic cell Acquired poor clearance of apoptotic bodies Genetic and epigenetic factors _Macrophage Diminished phagocytic capacity by macrophages Release of nuclear components Circulating antibodies Circulating immune complexes Kidney Chronic inflammatory

process Innate immune _{system response}

Local inflammation and cytokine release

Immune complex glomerular deposition (1) GBM (2) Mesangium (3) Interstitium (4) PTECs

Bowman’s capsule Capsular epithelium Efferent arteriole Afferent arteriole Podocyte Proximal tubule Glomerular capillary Lumen of Bowman’s capsule Subendothelium Distal tubule Proteases Subendothelial IC deposition Endothelial injury and proliferation Dendritic cells Release of type 1 interferon Adaptive

immune response _Dendritic cell Release of type 1 interferon

B lymphocyte LTh1 LTh2 LTh3 Amplification of lymphocyte B cell response Epithelial glomerular proliferation and fibrosis Lh17

Figure 1: Lupus nephritis: an imbalance between cytokine homeostasis and immune complex deposition. In predisposing susceptible individuals who develop systemic lupus erythematosus (SLE), there is an acquired poor clearance of apoptotic bodies and a diminished phagocytic capacity by macrophages (1). Early formation of immune complexes (ICs) include antinucleosomes, anti-double-stranded DNA (anti-dsDNA), DNA extractable nuclear antigen antibodies (ENAS), antibodies against C1q complex of the complement system, free DNA, antiribonucleoproteins (anti-RNP), and histones as byproducts of inefficient phagocytosis of apoptotic bodies (2). Circulating ICs are deposited initially at the glomerular base membrane (GBM), mesangium, and interstitial tissue within the proximal tubular epithelial cells (PTECs) (3) and (4). The deposited ICs initiate the release of proinflammatory cytokines and chemokines such as monocyte chemoattractant protein 1 (MCP-1), interleukins 1 and 6 (IL-1, IL-6) and adhesion molecules (CAMs) thus establishing a chronic inflammatory process (5). The resulting overload of the mesangial phagocytic system (innate immune system) leads to deposits of subendothelial ICs becoming an easy target for monocyte migration and infiltration and generating endothelial injury and proliferation (6) and (7). In turn, the adaptive immune system is activated secondary to the presence of ICs and dendritic cells (DCs) (8), which subsequently trigger release of type 1 interferon and induce maturation and activation of infiltrating T cells. This activation leads to sequential amplification of T helper 2 lymphocytes (Th2), T helper 1 (Th1), and T helper 17 (Th17) (9). Each of these amplifies lymphocyte B cell response and further activates macrophages, generating a second general response, which increases recruitment of effector cells that can no longer be modulated by regulatory T cells and resulting in the end in epithelial glomerular proliferation and fibrosis (10).

more important in the activation of previously differentiated effector T cells. An induced deficiency of ICOS reduces autoantibody titers of IgG and in situ survival of T cells but does not affect the condition [16].

Natural inhibitors of the CD28/B7 pathway include the cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor in T cells and PD-1. Both of these recruit inhibitor protein ty- rosine phosphatase (SHP-2). PD-1 chronically inhibits acti- vated T cells and makes them respond in peripheral tissues but not in lymphoid organs. This is essential in maintaining T cell tolerance. The fine control between T regulator cells and PD-1 pathway may depend on the completion of an un- controlled reactive autoimmune response [17]. The PD-1

pathway has the ability to simultaneously remove self- reactive T cells and promote the development of LT regulator cells.

4. Genetic Susceptibility of SLE

Patients with SLE have defects in all branches of the immune system including innate immunity, antigen presentation, apoptosis, impaired tolerance in T and B cells, and defective release of regulatory cytokines and chemokines. SLE should be considered a failure of immune tolerance in one or more of the central or peripheral checkpoints with summation effects of multiple genes related to the immune response [18].

(1) Défaut d’élimination des cellules apoptotiques et/ou nécrotiques et diminution des capacités phagocytaires macrophagiques : implication des protéines C1q, MBL et ficolines-2 et-3.

(2) Libération d’autoantigènes issus de deux sources principales :

- autoantigènes intracellulaires (nucléosomes et ADN) issus de débris apoptotiques et/ou nécrotiques mal éliminés ou,

- excès de NETs issus d’un défaut dans leur dégradation : implication de C1q.

(3) Formation de CIC par attaque d’auto-anticorps (anti-nucléosomes, anti-ADN et anti-NETs) : implication de C1q dans leur reconnaissance et leur fixation.

(4) Dépôt de CIC* suite leur accumulation dans la circulation générale. Défaut d’élimination des CIC : implication de

CR1 et CR3 à la surface, respectivement, des érythrocytes et des macrophages et/ou PNN et implication de C1q.

* anticorps anti-ADN/ADN

* anticorps anti-nucléosomes/nucléosomes * anticorps anti-NETs/NETs

* anticorps anti-C1q/C1q

(5) Activation de la voie Classique du complément. Implication de la voie Alterne.

(6 et 7) Formation du complexe d’attaque membranaire entrainant la libération de cytokines pro-inflammatoires et chimiokines. Recrutement et activation des cellules inflammatoires infiltrantes (monocytes, macrophages, PNN). Production de protéases, d’espèces réactives oxygénées à l’origine des lésions rénales.

(8) Activation des cellules dendritiques infiltrantes (CDs) et production d’IFN-alpha par les cellules dendritiques plasmacytoides activées (CDp) : implication de C1q.

(9) Modulation de la réponse immune : activation des lymphocytes B autoréactifs et production d’auto-anticorps ; activation des lymphocytes T autoréactifs entrainant la production de cytokines pro-inflammatoires ; entretien du processus inflammatoire chronique ou « cercle vicieux » auto-immun.

PARTIE 2 : TRAVAIL EXPERIMENTAL