There are three major forms of programmed cell death: apoptosis, pyroptosis and necroptosis. Apoptosis is a noninflammatory, “immunologically silent” form of programmed death, wherein a cell undergoes condensation of its nucleus and cytoplasm, chromatin is cleaved into nucleosome-sized fragments and the dying cell is packaged into noninflammatory apoptotic bodies. It is of central importance in the immune system. Pyroptosis and necroptosis are pathway-dependent, lytic, inflammatory programmed cell death pathways that allow the release of inflammatory mediators and antigens that may be involved in the clearance of some pathogens. In this chapter we will largely address the relevance of apoptosis in immunology.

Pathways of Apoptosis

There are two major pathways of apoptosis (Fig. 1), both of which have been implicated in the development and function of the immune system.

 • The mitochondrial (or intrinsic) pathway is involved in cell death during cell selection events in lymphocyte development and in diverse responses to stress and damage regulated by the BCL-2 family of proteins, named after the founding member, BCL-2, which was discovered as an oncogene in a B-cell lymphoma and shown to inhibit apoptosis. Some members of this family are pro-apoptotic and others are anti apoptotic. The pathway is initiated when cytoplasmic proteins of the BCL-2 family that belong to the BH3-only subfamily (so called because they contain one domain that is homologous to the third conserved domain of BCL-2) are induced or activated as a result of growth factor deprivation, noxious stimuli, DNA damage, or certain types of receptor-mediated signaling (e.g., strong signals delivered by self antigens in immature lymphocytes). BH3-only proteins are sensors of cell stress that bind to and influence death effectors and regulators. In lymphocytes, the most important of these sensors is a protein called BIM. Activated BIM binds to two pro-apoptotic effector proteins of the BCL-2 family called BAX and BAK, which oligomerize and insert into the outer mitochondrial membrane, leading to increased mitochondrial permeability. Growth factors and other survival signals induce the expression of antiapoptotic members of the BCL-2 family, such as BCL-2 and BCL-XL , which function as inhibitors of apoptosis by blocking BAX and BAK and thus maintaining intact mitochondria. BH3-only proteins also antagonize BCL-2 and BCL-XL . When cells are deprived of survival signals, the mitochondria become leaky because of the actions of the BH3-only protein sensors and BAX and BAK effectors and the relative deficiency of antiapoptotic proteins such as BCL-2 and BCL-XL . The result is that many mitochondrial components, including cytochrome c, leak out into the cytosol and activate cytosolic enzymes called caspases.

Fig1. Pathways of apoptosis. Apoptosis is induced by the mitochondrial and death receptor pathways, described in the text. The executioner caspases activate endonucleases and other enzymes, whose actions culminate in fragmentation of the dead cell, and the apoptotic bodies are cleared by phagocytes. FAS-L, FAS ligand; TNF, tumor necrosis factor.

Caspases are so named because they are Cysteine dependent ASPartyl proteASES. They use cysteine in the active site and cleave after aspartate residues. Most caspases are involved in apoptosis, but caspase 1, 4, and 6 in humans (corresponding to caspase 1 and 11 in rodents) contribute to inflammasome activation and pyroptosis. Cytochrome c binds to a cytosolic protein called APAF-1, which then oligomerizes and activates procaspase-9, yielding active caspase-9. Caspase-9 in turn cleaves and thereby activates downstream “executioner” caspases (most prominently caspase-3) that induce nuclear DNA fragmentation and other changes that culminate in apoptotic death.

• In the death receptor (or extrinsic) pathway, cell surface receptors of the TNF receptor superfamily are engaged by their TNF superfamily ligands. This pathway is involved in the elimination of unselected germinal center B cells. The receptors oligomerize and activate cytoplasmic adaptor proteins, which assemble procaspase-8, which cleaves itself when oligomerized and produces active caspase-8. The active caspase-8 cleaves downstream caspases, again resulting in apoptosis. In T cells, the most important death receptor is FAS (CD95), and its ligand is FAS ligand (FAS-L). FAS is a member of the TNF receptor family, and FAS-L is homologous to TNF. In many cell types, caspase-8 cleaves and activates a protein called BID. Truncated BID (tBID) is a BH3 only protein that binds to BAX and BAK and induces apoptosis via the mitochondrial pathway. Thus, the mitochondrial pathway may serve to amplify death receptor signaling.

In cells undergoing apoptosis, executioner caspases cleave and activate various protein substrates that then contribute to chromatin condensation, the fragmentation of the nucleus and cytoplasm, the cleavage of DNA into nucleosome-sized fragments, and the pacakaging of the dying cell into membrane-bound structures called apoptotic bodies. There are also biochemical changes in the plasma membrane, including the exposure of lip ids such as phosphatidylserine, which is normally on the inner face of the plasma membrane. These alterations are recognized by receptors on phagocytes, and apoptotic bodies and cells are rapidly engulfed and eliminated, without ever having elicited a host inflammatory response. This process is called efferocytosis. Furthermore, phagocytosis of apoptotic cells may induce the production of antiinflammatory mediators by macrophages.

Apoptosis in Lymphocyte Development and Function

The regulation of apoptosis contributes to the positive and negative selection of developing lymphocytes, can later contribute to the elimination of self-reactive mature lymphocytes, and is the mechanism by which cytotoxic T cells and NK cells kill infected cells and tumors.

During B- and T-cell development, cells are positively selected when they make functional preantigen receptors and antigen receptors, as described in Chapter 8. Survival is induced largely by the induction of antiapoptotic members of the BCL-2 family. Self-reactive lymphocytes undergo negative selection during development and are eliminated by the induction of an active form of BIM. Following immune responses, activated (effector) lymphocytes die because they are deprived of survival signals and the mitochondrial pathway of apoptosis is activated. By contrast, memory lymphocytes survive for extended peiods of time by the induction of high levels of BCL-2. Cytotoxic T cells and NK cells execute their targets by apoptosis, in particular by delivering enzymes called granzymes into the cytosol of target cells. As will be discussed in Chapter 11, granzyme B is a serine protease that cleaves after aspartates (much like caspases) and can cleave and activate executioner caspases such as caspase-3 and thus induce apoptotic death.

The best evidence for the involvement of the two apoptotic pathways in the elimination of mature self-reactive lymphocytes is that genetic ablation of either in mice results in systemic auto immunity, and the disease is more severe if both pathways are dis abled. Mutations of FAS, FAS-L, or downstream caspases cause a human autoimmune disease called autoimmune lymphoproliferative syndrome (ALPS). These two death pathways may function in different ways to maintain self-tolerance.

Peripheral T cells that recognize self antigens in the absence of costimulation may induce apoptosis by the mitochondrial pathway. In normal immune responses, the responding lymphocytes receive signals from the TCR, costimulators, and growth factors. These signals stimulate the expression of antiapoptotic proteins of the BCL-2 family (BCL-2, BCL-XL) and thus prevent apoptosis and promote cell survival, the necessary prelude to proliferation. When T cells avidly recognize self antigens, they may activate BIM, which triggers death by the mitochondrial pathway, as described earlier. At the same time, because of the relative lack of costimulation and growth factors, the antiapoptotic members of the BCL-2 family remain at low levels, and the actions of the effectors BAX and BAK are thus not counteracted.

Repeated stimulation of some T cells, particularly Th1 cells, results in coexpression of the death receptor FAS and its ligand FAS-L, and engagement of FAS triggers apoptotic death. When T cells are repeatedly activated, both FAS and FAS-L are expressed on the cell surface, and binding of the ligand to the receptor activates a cascade of caspases, which ultimately cause the apoptotic death of the cells.

اخر الاخبار

اخبار العتبة العباسية المقدسة

قسم الشؤون الخدمية ينفذ حملة لتنظيف الشوارع المحيطة بصحن مرقد أبي الفضل العباس (عليه السلام)

وفد العتبة العباسية المقدسة يزور شعبة الإعداد البدني للاطّلاع على برنامج تأهيل المنتسبين الجدد

قسم بين الحرمين يقدم جهودًا مضاعفة لإعادة المفقودات إلى الزائرين

بعد برامج تدريبية متخصصة.. متحف الكفيل يبيّن منجزات ملاكاته في فن الخاتم (الأرابيسك)

المزيد

الآخبار الصحية

ماذا يحدث إذا تناولنا الطعام مرة واحدة فقط في اليوم

اكتشاف عوامل خطر غير متوقعة لمرض الكبد الدهني

فيروس هانتا والسفينة الموبوءة.. تحديث من الصحة العالمية

طبيب يحسم الجدل السجائر الإلكترونية وعلاقتها بالسرطان

المزيد

الآخبار التكنلوجية

لأول مرة في الولايات المتحدة.. تشغيل مفاعل مصغر نووي يغذي الذكاء الاصطناعي بالطاقة

الكشف عن تفاصيل أول عملية ناجحة لاستعادة انتاج الحيوانات المنوية

أطلس يكشف خفايا الجسم البشري بدقة أرفع بـ50 مرة من شعر الإنسان

المتحف المصري الكبير يتحول إلى "أيقونة خضراء" بدعم ياباني

المزيد

مواضيع ذات صلة

Double Antibody Sandwich ELISA (DAS ELISA)

Enzyme Immunosorbent Assays

Antibody Structure and Function

The Major Proinflammatory Cytokines of Innate Immunity: Interleukin-6

The Major Proinflammatory Cytokines of Innate Immunity: Interleukin-1

The Major Proinflammatory Cytokines of Innate Immunity: Tumor Necrosis Factor

The Immune Receptor Family

Collectins and Ficolins

Soluble Effector Molecules of Innate Immunity: Pentraxins

Soluble Effector Molecules of Innate Immunity : The Complement System

MHC Genes

Cytokine-Producing Innate Lymphoid Cells