Immune System Function PDF

**Immune System Function** Introduction The immune system functions to protect the body from diseases by defending against potentially harmful agents such as pathogens, toxins, and cancer cells. The body employs various types of external (surface) barriers to keep foreign materials from entering t...

**Immune System Function** Introduction The immune system functions to protect the body from diseases by defending against potentially harmful agents such as pathogens, toxins, and cancer cells. The body employs various types of external (surface) barriers to keep foreign materials from entering the body. If these barriers fail to prevent the entry of harmful agents, the body responds with internal defenses, which include rapid, nonspecific (**innate**) defenses and slower, specific (**adaptive**) defenses. The innate defenses are nonspecific in that they are not directed at particular pathogens, whereas the adaptive defenses are specifically targeted. Furthermore, activation of nonspecific defenses does not result in **immunological memory** (ie, a substantial increase in the ability of the defenses to respond to future attacks by the same pathogen), whereas activation of specific defenses does result in such memory. Consequently, specific defenses adapt and become more efficient at eliminating specific pathogens over time upon repeated exposure to the same pathogen. This lesson covers immune system functions, including innate defenses and various types of acquired immunity. 20.2.01 External Innate Defenses The body\'s **innate defenses**, which include the external (surface) structures that provide the body\'s first line of defense, are present at birth. The [skin](javascript:void(0)) and [mucous membranes](javascript:void(0)) that collectively form the body\'s external surface act as physical barriers to pathogen entry into the body and secrete various substances that enhance this barrier function. The structural basis for the skin\'s barrier function is discussed in Concept 19.2.01. Some secretions produced by the skin and mucous membranes create environments unfavorable to pathogens at the body\'s surface (see Figure 20.6). Sweat and sebum (oil) produced by the skin cause the skin to have a slightly [acidic pH](javascript:void(0)), which inhibits bacterial growth. [Gastric juice](javascript:void(0)), secreted by the mucous membrane that lines the stomach, is very acidic and contains protein-digesting enzymes, resulting in an environment within the stomach that destroys most swallowed pathogens. Various defensive proteins and peptides also contribute to the external barriers. **Mucin** is a protein that dissolves in water to form a sticky fluid called **mucus**, which helps protect the body by trapping pathogens, particularly in the respiratory, digestive, and urogenital tracts. The enzyme **lysozyme**, which kills bacteria by disrupting bacterial cell walls, is secreted into saliva, tears, and respiratory mucus. In addition, **defensins**, peptides produced by epithelial cells and various immune cells, can destroy a variety of pathogens, including bacteria, viruses, and fungi. Similarly, sweat contains **dermcidin**, a peptide that kills bacteria and fungi. Chapter 20: Immune System 618 **Figure 20.6** Components of the external innate defenses. The physical and chemical defenses that operate at the body\'s surface are supplemented by mechanical mechanisms that help move pathogens away from the body. **Cilia**, located on cells of the [upper](javascript:void(0)) [respiratory tract](javascript:void(0)), sweep mucus (and trapped pathogens) upward toward the mouth, where pathogens can be swallowed and destroyed by gastric juice. In addition, tears and saliva help wash pathogens from the surface of the eyes and oral cavity, respectively, and the outward flow of urine from the body helps remove pathogens from the lower urinary tract. 20.2.02 Internal Innate Defenses Pathogens that evade the body\'s external innate defenses (described in the previous concept) are quickly met by internal innate defenses. Like external defenses, internal innate defenses are not directed at specific pathogens, but rather respond to a broad range of microorganisms, potentially harmful foreign substances, and abnormal (eg, cancerous) body cells. Some body cells possess receptors called **pattern recognition receptors (PRRs)**, which bind to classes of molecules called **pathogen-associated molecular patterns (PAMPs)**. PAMPs are typically present on microorganisms and viruses but not on healthy human cells. Binding of PAMPs to PRRs results in the activation of internal innate defenses. A person\'s body with labeled organs Description automatically generated Chapter 20: Immune System 619 Two types of leukocytes that play significant roles in innate immunity are [macrophages](javascript:void(0)) (derived from monocytes) and [neutrophils](javascript:void(0)). Macrophages and neutrophils both engage in **phagocytosis**, a process by which pathogens are engulfed by defensive cells and destroyed. Pathogens or other materials engulfed by phagocytes (ie, phagocytic cells) are enclosed within vesicles (phagosomes) into which hydrogen ions are pumped. The resulting acidified phagosomes fuse with [lysosomes](javascript:void(0)) to form phagolysosomes, which contain **hydrolytic enzymes**. The engulfed materials within the phagolysosomes are digested and destroyed by these enzymes, as shown in Figure 20.7. **Figure 20.7** Destruction of a pathogen via phagocytosis. In addition to destroying pathogens via phagocytosis, macrophages and neutrophils both perform other defensive functions. For example, macrophages participate in the activation of lymphocytes involved in adaptive immune responses, and neutrophils can undergo **degranulation**, a process by which granulocytes secrete the contents of various cytoplasmic granules via [exocytosis](javascript:void(0)). Degranulation results in the release of a variety of defensive substances, including antimicrobial molecules such as defensins, as well as [cytokines](javascript:void(0)) (chemical signals) that help regulate the immune response. Other leukocytes, including [natural killer (NK) cells](javascript:void(0)), mast cells, basophils, and eosinophils, also contribute to innate defenses. Although NK cells are not phagocytic, they can induce virus-infected cells and cancer cells to destroy themselves via [apoptosis](javascript:void(0)). Furthermore, mast cells, basophils, and eosinophils are granulocytes that participate in multiple immune system activities, including the **inflammatory response**, defense against parasites, and allergic reactions. Mast cells promote inflammation by releasing histamine, which triggers vasodilation and increased capillary permeability, as depicted in Figure 20.8.  Chapter 20: Immune System 620 **Figure 20.8** Events of the inflammatory response. The actions of various antimicrobial proteins enhance the internal innate defenses. **Interferons** are proteins produced by virus-infected cells that interfere with viral replication in other cells and participate in regulating leukocyte activity. **Complement** (ie, a collective term referring to the complement system) is composed of more than 30 different proteins. Upon activation, complement increases phagocyte efficiency and helps regulate the inflammatory response. Activated complement also forms membrane attack complexes (MACs), which insert into pathogen cell membranes, forming pores that cause pathogen lysis. A diagram of a cell Description automatically generated Chapter 20: Immune System 621 20.2.03 Adaptive Immunity In contrast to the innate defenses, which are nonspecific, the mechanisms responsible for **adaptive immunity** (ie, **cell-mediated immunity** and **humoral immunity**) are specific, in that they are directed at particular pathogens. Each different pathogen possesses distinct **antigens**, which are specific molecules (typically [proteins](javascript:void(0)) or [polysaccharides](javascript:void(0))) that trigger an immune response by being recognized as foreign by the cells of the adaptive immune system. Adaptive immunity depends on the activity of lymphocytes, namely T lymphocytes (T cells) and B lymphocytes (B cells). T and B cells have surface receptors that bind to specific antigens, and each of these cells possesses a great number of antigen receptors. All receptors on a single cell have the same specificity, so each T cell and B cell can recognize and respond to only one particular antigen. However, due to the large number of lymphocytes with unique receptors in each individual, the total number of different antigens to which a person can respond is very great. **Naïve lymphocytes** (ie, mature lymphocytes that have yet to encounter antigens to which they can respond) must be activated before they can fight an invader. This activation happens only to lymphocytes that possess receptors that bind the invader\'s antigens. Consequently, only a small fraction of naïve lymphocytes in an individual are activated by a particular pathogen. Upon activation, each of these responsive lymphocytes proliferates to form a large number of cells identical to itself (ie, a clone). This process of activating and replicating only cells capable of responding to a particular antigen is called **clonal selection** (Figure 20.9). **Figure 20.9** Process of clonal selection.  Chapter 20: Immune System 622 Following the proliferation of a particular lymphocyte, most cells in the resulting clone differentiate into **effector cells** that immediately function in combating the pathogen that stimulated clone production. The remaining cells of the clone differentiate into long-lived **memory cells**, which are held in reserve. The initial activity of the adaptive immune system to a new pathogen is called a **primary immune response**, and subsequent responses to the same pathogen are called **secondary immune responses**. Memory cells are the basis for immunological memory, which allows specific immune responses to be adaptive. The presence of previously formed memory cells causes specific defenses to be faster and more effective in response to second or subsequent infections by a particular pathogen, as shown in Figure 20.10. **Figure 20.10** Effect of memory cells on specific immunity. 20.2.04 Antigen Presentation Adaptive immune responses require lymphocyte activation, a process dependent on recognition and binding of foreign antigens by B-cell and T-cell receptors. Antigen receptors on B cells can recognize and bind unaltered, isolated antigens. However, T-cell receptors recognize antigens only when the antigens are processed and displayed on the surface of cells via membrane proteins called **major histocompatibility complex (MHC) proteins**. The process by which antigens are displayed in association with MHC proteins on cells is called **antigen presentation**. There are two classes of MHC proteins. Class I MHC proteins (MHC I) are present on all nucleated cells, whereas class II MHC proteins (MHC II) are located only on **antigen-presenting cells (APCs)**, which include dendritic cells, [macrophages](javascript:void(0)), and B cells. MHC I molecules typically display fragments of antigens produced within the cell presenting them. These antigens can be normal (self) antigens in a healthy cell or foreign antigens, such as viral proteins produced in a cell during a viral infection. A diagram of a normal immune response Description automatically generated with medium confidence Chapter 20: Immune System 623 Conversely, MHC II proteins typically display fragments of foreign antigens that were taken into APCs via phagocytosis (Figure 20.11). **Figure 20.11** Role of MHC proteins in antigen presentation. 20.2.05 Cell-Mediated Immunity The adaptive immune system defends against intracellular pathogens (including [viruses](javascript:void(0)) and certain bacteria), cancer cells, and foreign cells (eg, cells of transplanted organs) primarily through **cell-mediated immunity**. This type of immunity depends on the function of multiple types of T cells (so named because they mature in the thymus). In particular, T cells called **cytotoxic T (TC) cells** (also known as CD8+ cells) function as effector cells directly responsible for destroying infected or abnormal body cells. T cell activation requires interactions between naïve T cells and antigen-presenting cells (APCs). Such interactions typically occur in [lymph nodes](javascript:void(0)) or the spleen. A type of T cell called a **helper T (TH) cell** (or CD4+ cell) becomes activated when the TH cell is presented with a foreign antigen, in association with MHC II, on the surface of an APC (eg, dendritic cell). If the antigen receptors of the TH cell can recognize and bind specifically to the presented antigen, the TH cell becomes activated and replicates to form a clone of the activated TH effector cells, as depicted in Figure 20.12.  Chapter 20: Immune System 624 **Figure 20.12** Activation and replication of TH cells. Clones of TH effector cells participate in activating naïve TC cells that possess receptors capable of binding the specific foreign antigen that originally stimulated TH cell activation, which is presented (along with MHC I) to the TC cells by APCs. TH cells stimulate the APCs to present additionally required (ie, co-stimulatory) molecules to the TC cells, completing TC cell activation. The activated TC cells are then stimulated by cytokines (secreted by the TH cells) to divide and form a clone of TC effector and memory cells. When TC effector cells subsequently encounter body cells displaying the targeted antigen (on MHC I), the TC cells release cytotoxins to induce these abnormal cells to undergo apoptosis (Figure 20.13). A diagram of a cell activating process Description automatically generated Chapter 20: Immune System 625 **Figure 20.13** Steps in cell-mediated immunity. In addition to TH and TC cells, some T cells differentiate into **regulatory T (TReg) cells**, which function to inhibit the immune response. TReg cells play an important role in preventing overactive immune responses, such as those directed against self-antigens (ie, autoimmune responses), which inflict damage on healthy tissues. This topic is discussed in greater detail in Concept 20.2.08.  Chapter 20: Immune System 626 20.2.06 Humoral Immunity In addition to cell-mediated immunity, which results from the activity of cytotoxic T cells, adaptive immunity involves **humoral immunity**, which requires the participation of **B cells** (ie, lymphocytes that mature in the bone marrow). Humoral immunity ultimately depends on the function of specialized protein molecules called **antibodies**, which are secreted by activated B cells. For this reason, humoral immunity is also referred to as **antibody-mediated immunity**. A humoral immune response begins with activation and proliferation (ie, clonal selection) of naïve B cells that possess antigen receptors capable of binding specific foreign antigens present on an invading pathogen. B-cell antigen receptors have essentially the same structure as secreted antibodies; however, these antibody-like receptor molecules are anchored to the B cell membrane. Some antigens (ie, T cell-independent antigens) induce B cell activation without helper T (TH) cell involvement. However, most antigens (ie, T cell-dependent antigens) provoke B cell responses via a mechanism that requires TH cell participation. B cells function as antigen-presenting cells, and in doing so, B cells facilitate their own activation by TH cells. When B-cell receptors bind their targeted antigens, the bound antigens can be taken up by B cells via [endocytosis](javascript:void(0)). After being internalized, the antigens are processed and displayed on the B cells\' surface by class II major histocompatibility complex (MHC II) proteins, which allows the antigens to be presented to nearby TH cells. In turn, these TH cells secrete cytokines that stimulate replication and differentiation of the antigen-activated B cells into **plasma cells** and memory cells (Figure 20.14). Chapter 20: Immune System 627 **Figure 20.14** Steps in T-cell dependent activation of B cells. Plasma cells, which contain abundant [rough endoplasmic reticulum](javascript:void(0)), are specialized to secrete large numbers of antibody molecules (ie, immunoglobulins \[Ig\]). Each antibody consists of four [polypeptide](javascript:void(0)) chains, including two identical heavy chains and two identical light chains. Each of these chains possesses a variable region and a constant region, and the chains are linked by disulfide bonds to produce a flexible Y-shaped protein. The tips of the two arms of the Y, which are formed by the heavy and light chain variable regions, are identical. These tips on the antibody serve as specific antigen-binding sites, as shown in Figure 20.15. A diagram of a cell cycle Description automatically generated Chapter 20: Immune System 628 **Figure 20.15** Antibody structure and interaction between antibody and antigen. Antigens are large molecules that typically possess numerous specific sites to which antibodies can bind. These sites are referred to as **antigenic determinants**, or **epitopes**, whereas antigen-binding sites on antibodies are called **paratopes** (Figure 20.15). All antibodies secreted by a particular plasma cell have the same antigen specificity (ie, bind the same epitope), and this specificity is identical to that of the antigen receptors present on the original naïve B cell that was activated to form the plasma cell. There are five general classes of antibodies: IgG, IgA, IgM, IgE, and IgD. These classes have different structural and functional characteristics that allow different classes to play specialized roles in varied aspects of the humoral immune response. Antibodies typically function in defense against extracellular threats, such as bacteria, fungi, toxins, parasites, and free viruses. However, antibodies do not destroy such invaders directly, but rather inactivate and mark foreign antigens for destruction by other components of the immune system. Various mechanisms of antibody defensive functions are summarized in Table 20.2.  Chapter 20: Immune System 629 **Table 20.2** Mechanisms by which antibodies function in defense of the body. 20.2.07 Immune Response Integration Different pathogens (eg, bacteria, viruses, parasites) present different challenges to the body\'s defenses. However, successful defense against any pathogen typically requires an integrated immune response that involves both [innate](javascript:void(0)) and [adaptive](javascript:void(0)) immune mechanisms operating in a coordinated manner (see Figure 20.16 and Table 20.3). A chart of a cell structure Description automatically generated with medium confidence Chapter 20: Immune System 630 **Figure 20.16** Integration of defensive mechanisms.  Chapter 20: Immune System 631 **Table 20.3** Roles of components shown in Figure 20.16. Macrophages and dendritic cells play key roles in both innate immunity (ie, as active phagocytes) and adaptive immunity (ie, as antigen-presenting cells), and they therefore serve to functionally link the innate and adaptive defenses. Likewise, antibodies produced via an adaptive immune response can facilitate innate immunity by activating complement and by coating pathogens (ie, acting as **opsonins**), which enhances phagocyte function. In addition to the integration that exists between innate and adaptive defensive mechanisms, the combined participation of both cell-mediated and antibody-mediated (ie, humoral) adaptive immunity is essential for defeating many pathogens. For example, the activity of cytotoxic T cells, as well as antibodies, is necessary to eliminate pathogens (eg, viruses) that reside both inside and outside of body cells. A table with text on it Description automatically generated Chapter 20: Immune System 632 **Concept Check 20.2** The following flowchart depicts steps in an integrated adaptive immune response directed against an invading pathogenic virus. Complete the flowchart by determining which of the following phrases belongs in each blank box: \"Antigen presentation,\" \"B cell activation,\" \"Cytotoxic T cell activation,\" \"Destruction of virus-infected body cell,\" \"Helper T cell activation,\" \"Neutralization of extracellular viruses,\" \"Phagocytosis of virus.\" [**Solution**](javascript:void(0)) 20.2.08 Autoimmunity To function properly, an individual\'s immune system must be able to distinguish between **self-antigens** (ie, autoantigens), which are normal components of the individual\'s own healthy cells, and **foreign antigens**. As illustrated in Concept 20.1.03, autoreactive lymphocytes (ie, T and B cells that possess antigen receptors capable of strongly binding autoantigens) are typically [eliminated](javascript:void(0)) or rendered inactive during immune system development. However, in some cases the immune system fails to tolerate autoantigens, and instead mounts an immune response against these antigens, a situation referred to as **autoimmunity**. During an autoimmune response, autoreactive antibodies (ie, autoantibodies) and autoreactive cytotoxic T (TC) cells cause destruction of healthy cells in the body, which can result in an autoimmune disease (eg, multiple sclerosis, type 1 diabetes mellitus). Regulatory T (TReg) cells that function to suppress the immune response are important for limiting autoimmune responses (see Figure 20.17). Therefore, TReg dysfunction is commonly observed in individuals with autoimmune diseases.  A diagram of a structure Description automatically generated with medium confidence