Elsevier

Life Sciences

Volume 72, Issue 25, 9 May 2003, Pages 2803-2824
Life Sciences

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Role of inherited defects decreasing Fas function in autoimmunity

https://doi.org/10.1016/S0024-3205(03)00196-6Get rights and content

Abstract

Fas is a death receptor belonging to the TNFR superfamily and induces cell apoptosis by both activating a caspase cascade and altering mitochondria. In the immune system, Fas is involved in the switching-off of the immune responses and cell mediated cytotoxicity. In humans, genetic defects decreasing Fas function cause the Autoimmune Lymphoproliferative Syndrome (ALPS) where autoimmunities are associated with accumulation of polyclonal lymphocytes in the secondary lymphoid tissues and expansion of T cells lacking both CD4 and CD8 (DN cells). Expansion of DN cells is absent in an ALPS variant, named Dianzani's Autoimmune Lymphoproliferative Disease (DALD). The observation that DALD patients' families display increased frequency of autoimmune diseases different from ALPS suggests that defects of Fas function may also play a role in development of “common” autoimmune diseases. This possibility is supported by detection of defective Fas function in substantial proportions of patients with the multiple autoimmune syndrome or aggressive forms of type 1 diabetes or multiple sclerosis. This article reviews data suggesting that development of autoimmune/lymphoproliferative patterns may involve several alterations hitting the Fas system, but might also involve alterations in other systems contributing to the switching-off or proliferation of lymphocytes.

Introduction

The specific immune response involves T and B lymphocytes activated by non selfantigens. B cells recognize every type of soluble macromolecules in their naive form, whereas T cells recognize peptides processed and presented on major histocompatibility complex (MHC) molecules expressed on the cell surface by antigen presenting cells (APC) (i.e. macrophages, dendritic cells and B lymphocytes). However, encounter of the antigen is not sufficient to activate lymphocytes and the two-signal model postulates that this requires two signals: “signal one” delivered by the antigen receptor and “signal two” by a costimulatory molecule [44], [50], [99]. Delivery of signal one alone induces cell anergy or apoptosis and peripheral tolerance to antigens. Signal two is delivered to T cells by APC activated by an inflammatory microenvironment and to B cells by activated T cells recognizing antigens presented by the B cell itself. Activation is accompanied by modifications of expression of several genes that code for surface molecules involved in lymphocyte proliferation and effector functions, which allow expansion of antigen-specific lymphocytes and their differentiation into effector cells, i.e. plasma cells secreting antibodies for B cells, activated T cells secreting cytokines for CD4+ T helper (TH) cells, and cytotoxic T lymphocytes (CTL) for CD8+ T cells. Activation also triggers expression of several genes coding for molecules involved in immune response switching-off, an active process that induces apoptosis of most effector lymphocytes several days later. A small subset of activated cells survives to form an expanded pool of memory lymphocytes and accounts for the more efficient response upon re-encounter of the same antigen (secondary response).

The deadly switching-off of immune responses is crucial to control the size of the peripheral lymphocyte pool, since this would otherwise expand as the outcome of further responses during life. Instead, the size of the peripheral pool does not change since 1) most effector lymphocytes are eliminated by the switching-off process and 2) the moderate expansion of memory cells is compensated by decreasing the size of the naı̈ve lymphocyte pool. Moreover, switching-off is probably crucial to reduce the risk of autoimmunities deriving from cross-reactivity between non-self and self antigens [7], [75]. The molecular mimicry model, in fact, assumes that these cross-reactions play a crucial role in autoimmunity and is based on the observation that many viral proteins comprise peptide sequences similar to those of self proteins. The model depicts that after elimination of the invader, the immune system may continue to act against the cross-reacting self molecules and induce an autoimmune disease. Therefore, a biological clock controlling the duration of immune responses would decrease the risk of these cross-reactions.

In the immune system, apoptosis is an essential feature of lymphocyte education in primary lymphoid organs through the negative selection of potentially autoreactive cells, and the effector function of cytotoxic cells that use several mechanisms to trigger apoptosis of their target cells.

Apoptosis is morphologically characterized by plasma membrane blebbing, cell shrinkage, chromatin condensation, and disassembly of the cell into multiple membrane-enclosed bodies [150]. In most cell types, internucleosomal DNA degradation accompanies these changes [41], [151]. Apoptotic bodies are then phagocytized by macrophages expressing receptors for molecules specifically expressed by apoptotic membranes. Apoptosis may be triggered by the absence of survival signals (apoptosis by neglect) [9], [160], or by several “death receptors” (apoptosis by death receptors) [116], [143]. The best known death receptors are grouped in the tumor necrosis factor receptor (TNFR) superfamily and are engaged by molecules belonging to the tumor necrosis factor (TNF) superfamily. They mainly trigger apoptosis by activating a cascade of proenzymes called caspases (cysteine-dependent aspartate-directed proteases) [16], [53], [117]. Switching-off is partly due to withdrawal of growth factors necessary for lymphocyte survival, but also involves specific death receptors whose function is activated upon long-term cell activation. The best known of these receptor is Fas (Apo-1/CD95), a member of the TNFR superfamily.

Section snippets

Fas and other death receptors

The TNFR superfamily comprises more than 20 members (Table 1) [6] characterized by an extra-cellular domain containing 1–6 cysteine-rich domains (CRDs). It includes both death and growth receptors. Differences in their cytoplasmic tail are used to divide them into two groups that mostly display different functions.

The first group has a cytoplasmic motif called the “death domain” (DD) [60], [129], that interacts with DDs expressed by adaptor proteins involved in recruitment of the first caspase

Autoimmune lymphoproliferative syndromes

As mentioned earlier, switching-off of immune responses is crucial for the homeostasis of the peripheral lymphocyte pool size and to decrease the risk that effector cells recruited by non self antigens cross-react with self antigens. Inherited defects of this system naturally cause diseases characterized by accumulation of lymphocytes in the secondary lymphoid organs and autoimmunity.

This pattern was first shown in mice homozygous for the lpr(lymphoproliferation) or gld (generalized

A lesson from genetically modified mice

Data from ALPS and DALD patients suggest that ALPS development requires accumulation of several genetic defects hitting the Fas system and that some may also favour development of other autoimmune diseases, and/or cancer. Data on mouse models confirm that patterns partly similar to ALPS may be caused by several genetic defects hitting the Fas system and show that they may also be caused by alterations in other systems involved in either lymphocyte apoptosis or proliferation.

Conclusions

An increasing bulk of data show that inherited alterations of the Fas system, and probably of other receptor systems involved in the immune response switching-off, may be novel genetic factors involved not only in development of autoimmune/lymphoproliferative patterns, but also in general predisposition to autoimmunity. The complexity of the Fas system in terms of function and molecules involved enables mutations in many genes to directly or indirectly alter the system and contribute to

Acknowledgements

Supported by Telethon grant N. E1170 (Rome), Associazione Italiana Ricerca sul Cancro (A.I.R.C., Milan), MURST cofin-projects (Rome), AIDS Project (Istituto Superiore di Sanità, Rome), Fondazione Italiana Scelrosi Multipla (FISM, Genoa).

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