Adaptive immunity









  • Unlike the innate immune response, the adaptive immune response is characterized by specific antigen recognition and immunologic memory.



  • Lymphocytes are the key cell types of the adaptive immune response.



  • B lymphocytes differentiate into antibody-secreting plasma cells and are responsible for humoral immunity.



  • CD8 + T lymphocytes differentiate into cytotoxic T cells, which function to control viruses and other intracellular pathogens by directly killing infected cells.



  • CD4 + T lymphocytes differentiate into a myriad of helper T-cell subsets, which regulate and coordinate the overall immune response and span a spectrum from highly proinflammatory to potently immunosuppressive function.



The adaptive immune system is generally considered an additional line of defense after innate immunity. There are several important differences between the innate and adaptive immune systems (see also Chapters 100 and 101). First, adaptive immunity takes more time to develop than the rapid onset of inflammation induced by innate immune cells. Second, rather than the more nonspecific activation of innate immune cells by pattern recognition receptors, components of the adaptive immune system develop to recognize specific pathogens. Finally, immunologic memory is a hallmark of the adaptive immune system, which allows for a more rapid and robust immune response upon repeated exposure of the same pathogen. Although it is helpful to consider the innate and adaptive immune systems as distinct, in reality these two systems rely heavily on each other for activation and coordination of an overall immune response. Consequently, there is a great degree of crosstalk between the two systems, which will be highlighted throughout this chapter.


The primary cell types of the adaptive immune response are lymphocytes, which can be broadly classified into B cells and T cells. B cells differentiate into plasma cells and function primarily to produce antibodies, essential for humoral immunity. T cells, by contrast, differentiate into effector cells with a variety of functions, including killing infected cells, directing the activation or suppression of innate immune cells, promoting innate immune cell migration, and enhancing barrier and immunologic function of epithelial cells. This chapter focuses on the cellular components of adaptive immunity, beginning with a brief overview of B-cell and T-cell development, followed by a discussion of B-cell function and humoral immunity. Next, T-cell activation is discussed, followed by differentiation and function of CD8 + cytotoxic T cells and CD4 + T helper cells. The chapter concludes with an introduction to adaptive immunity in the intensive care unit (ICU).


Lymphocytes develop to recognize specific antigens


B cells and T cells are so named for their respective sites of maturation: bone marrow for B cells and thymus for T cells. The development of both cell types has many similarities, which result in a diverse repertoire of lymphocytes, each able to recognize a specific antigen. Both B and T lymphocytes arise from common lymphoid progenitors, which derive from hematopoietic stem cells. B cells develop in response to transcription factors EBF, E2a, and Pax-5, whereas the transcription factors NOTCH-1 and GATA-3 drive T-cell development. For both cell types, one of the earliest steps in development involves gene rearrangements in the antigen recognition regions of the immunoglobulin heavy-chain locus (B cells) or the T-cell receptor (T cells). This gene rearrangement process is necessary to develop a wide array of cells with specific antigen recognition regions. The next steps involve positive and negative selection, resulting in a final repertoire of cells capable of recognizing processed foreign antigen while not reacting to self-antigens. Immature B cells express immunoglobulin M (IgM) on their surface. If they bind strongly to self-peptides in the bone marrow, they are either depleted or undergo further gene rearrangements in a process called receptor editing . B cells that survive negative selection leave the bone marrow and migrate to peripheral lymphoid organs where they await activation and further maturation to antibody-secreting plasma cells.


Immature T cells undergo both positive and negative selection in the thymus. Positive selection is carried out in the cortex of the thymus, where T cells that recognize peptides presented by dendritic cell major histocompatibility complex (MHC) molecules survive. Negative selection occurs after positive selection and is carried out in the corticomedullary junction of the thymus. Here, T cells that have either a strong affinity or no affinity to self-peptides bound to MHC molecules are deleted by apoptotic cell death. Meanwhile, immature T cells with a weak affinity for self-peptides bound to MHC molecules survive. In this way, surviving T cells are capable of recognizing self-MHC molecules but do not react strongly to self-antigens. These surviving T cells (naïve T cells) leave the thymus and continuously circulate through and among peripheral lymphoid organs, making multiple contacts with resident antigen-presenting cells capable of T-cell activation.


B-cell activation leads to antibody secretion: The humoral immune response


The humoral immune response is driven by antibodies produced following the stimulation, proliferation, and differentiation of naïve B cells. Naïve B cells are activated in secondary lymphoid organs, such as local lymph nodes or the spleen, where they encounter processed protein fragments (antigens) bound to MHC class II proteins on the surface of professional antigen-presenting cells (APCs). Antigen recognition and subsequent B-cell activation often occur in the presence of specialized helper T cells, which facilitate and direct B-cell differentiation. Once activated by the overlapping signals provided by APCs and helper T cells, B cells proliferate and differentiate. Some B-cell clones develop into plasma cells, which are factories for high-level antibody production. Other clones differentiate into memory B cells, which are long lived and allow for the anamnestic nature of the secondary immune response whereby subsequent encounters with a pathogen lead to a faster, higher-magnitude antibody response. Although a B cell and its antibody products are specific to only a single antigen or epitope, it is important to note that any given microorganism contains many foreign proteins that are potentially antigenic. Indeed, an invading bacterium may contain dozens or hundreds of antigenic peptide sequences, each capable of stimulating a B cell (and likely a T cell). Thus, the majority of humoral immune responses are polyclonal, meaning that multiple B-cell populations are engaged in the response, and high titers of a wide variety of antibodies are produced, all of which are specific to the pathogen.


Antibodies, also called immunoglobulins , are the primary product of B cells and constitute the effector element of the humoral immune response. Fig. 101.1 depicts general immunoglobulin structure. The classic antibody is constructed of two heavy chains, bound to each other, and two light chains, each bound to a heavy chain. The variable regions of the heavy and light chains contribute to the formation of the antigen-binding site, also referred to as the antigen-binding fraction (Fab) segment . As their name suggests, variable regions differ among individual antibodies and are responsible for the specificity of the antibody response. The remaining antibody fraction is denoted the Fc portion (for crystallizable fraction).




• Fig. 101.1


Basic structure of the immunoglobulin molecule. (A) The stereotypical antibody has a general “Y” shape and is composed of two heavy chains and two light chains bound to each other by disulfide bonds. Both chains contain constant regions—constant heavy (C H ) and constant light (C L )—of conserved amino acid sequences, which are alike in all antibody molecules of the same class, and variable regions (V H and V L ), which are highly variable and unique to the antigen-binding site of each individual antibody. Sites of papain or pepsin proteolytic cleavage result in the Fab and Fc immunoglobulin fragments. (B) Immunoglobulin A (IgA) and immunoglobulin M (IgM) are polymeric antibodies composed of 2 (IgA) or 5 (IgM) basic immunoglobulin chain units.


Antibodies confer protection by two mechanisms: neutralization and opsonization ( Fig. 101.2 ). Neutralizing antibodies slow or halt infection by binding proteins, which confer virulence to the invading microorganism, such as a viral receptor, and preventing them from functioning. Neutralizing antibodies also protect the host by binding to secreted microbial toxins. This ability underlies lifesaving passive immunotherapies for toxin-mediated infections such as botulism and diphtheria. Opsonization is the process by which Fc receptors on the surface of innate immune effector cells bind the Fc portion of antigen-bound antibodies, facilitating phagocytosis and the killing of antibody-coated microorganisms. In addition to direct opsonization, the exposed Fc portion of bound antibodies also activates the complement cascade. Complement activation further augments the antiinfective response by either directly killing bacteria through assembly of the membrane attack complex or by further opsonization via complement proteins such as C3.




• Fig. 101.2


Direct and indirect antibody functions. Antibodies function to directly neutralize microbial virulence factors, such as virus receptors or bacterial toxins. Indirect antibody function includes complement activation and opsonization, whereby phagocytic cells recognize the Fc portion of pathogen-bound antibodies, prompting phagocytosis and microbial killing.


B cells produce antigen-specific antibodies with variations in structure that impact function. These different antibody classes, or isotypes, add important nuance to the adaptive immune response to infection. Changing the antibody produced by a B cell from one class to another is known as isotype switching or class switching and is mediated by a complex interplay of cytokines and helper T-cell interaction. Specific functions and characteristics of antibody classes are outlined in Table 101.1 . Of particular relevance is the temporal relationship between IgM and IgG in the context of new infection. In the primary immune response, in which the adaptive immune system recognizes a previously unencountered threat, the first class of antibody produced after B-cell activation is IgM. Over the course of the immune response, levels of IgM fall and are replaced by high levels of IgG. Subsequent exposure to the same pathogen generates high levels of IgG with a much shorter latency between antigen exposure and antibody production. This temporal relationship comes into play diagnostically when one obtains serologies, or infection-specific immunoglobulin levels, to diagnose infection.



TABLE 101.1

Characteristics of Antibody Isotypes








































Isotype (Class) Functions Subclasses Present in Secretions Placental Transfer



  • IgG




  • Opsonizes antigens for phagocytosis



  • Complement activation



  • Antibody-dependent cell killing by NK cells



  • Neonatal immunity via placental transfer




  • IgG 1



  • IgG 2



  • IgG 3



  • IgG 4




  • +



  • +



  • +






  • +++



  • +



  • +++



  • ++




  • IgM




  • Complement activation



  • Antigen recognition by naïve B cells

+
IgA


  • Mucosal immunity




  • IgA 1



  • IgA 2



  • sIgA




  • +



  • +



  • ++++








IgE


  • Mast cell degranulation

+
IgD


  • Antigen recognition by naïve B cells


Ig , Immunoglobulin; NK , natural killer cell.


Aside from their critical role in the adaptive immune response to infectious disease, antibodies have important roles in other aspects of human biology. Antibodies directed inappropriately against self-derived antigens (so-called autoantigens ) are key elements in the pathophysiology of autoimmune disease. A classic example is myasthenia gravis, in which autoantibodies bind to the neuromuscular junction, preventing stimulation of muscle fibers and resulting in weakness. Autoantibody-mediated autoimmune diseases are often treated with a combination of immunosuppressive medications and therapies that reduce antibody titer, such as therapeutic apheresis. Additionally, immunosuppressive therapies to prevent rejection of transplanted organs often involve maneuvers to reduce antibody production—for example, the B-cell-reducing agent rituximab.


Due to their ability to recognize and bind specific proteins, antibodies are increasingly used to develop targeted therapies, diagnostic assays, and a multitude of research tools. The development of technologies to generate and mass-produce monoclonal antibodies has created many new therapeutic agents and diagnostic tools. An example of monoclonal antibody use that has become ubiquitous in the modern practice of diagnostic medicine is the enzyme-linked immunosorbent assay (ELISA). This powerful tool involves the use of monoclonal antibodies that are specific to certain proteins of interest, such as anti–human immunodeficiency virus antibody. When exposed to a patient sample, the monoclonal antibodies will bind relevant material, if present, from patient blood or plasma. When secondary fluorescent antibody is applied, it is possible to detect and quantify the protein of interest. ELISA is just one of many examples of antibody-based techniques used in both clinical diagnostics and basic/translational research, including Western blot, flow cytometry, immunofluorescence assays, and others.


Effector t cells direct cell-mediated immunity


Like B cells, naïve T cells are activated in secondary lymphoid organs, where they proliferate and differentiate into either memory cells or effector T cells. Effector T cells migrate from lymphoid organs to sites of inflammation where they carry out a multitude of functions depending on effector cell type.


T-cell activation requires interaction with innate immune cells


As was the case with humoral immunity, proper interplay between the innate and adaptive immune systems is vital for activation of cell-mediated immunity. T cells are generally unable to respond to so-called free antigen but require contact with antigenic peptides that have been processed and displayed via MHC molecules on the cell surface. MHC class I molecules are expressed on all nucleated cells in the body and are recognized by CD8 + T cells. Effector CD8 + T cells (also known as cytotoxic T lymphocytes ) are designed to kill tumor cells and cells infected with intracellular microbes or viruses. By contrast, CD4 + T cells respond to peptide presented by MCH class II molecules. MCH class II molecules are found on specialized APCs. APCs are designed to capture antigen at the site of infection/injury, process it into small peptides, and transport it via the lymphatics for presentation to T cells in secondary lymphoid organs. There are two types of APCs: (1) professional APCs are innate immune cells that constitutively express MHC class II molecules and include dendritic cells, macrophages, and certain B lymphocytes; (2) nonprofessional APCs express MHC class II molecules only when stimulated by certain cytokines, such as interferon-γ (IFN-γ) and include endothelial and some epithelial cells. Because nonprofessional APCs are not efficient at processing antigen into MHC binding peptides, they likely contribute to a minority of T-cell responses. Dendritic cells, on the other hand, are highly effective professional APCs responsible for the majority of naïve T-cell activation.


Under normal circumstances, each T-cell receptor recognizes and binds to only a specific antigenic peptide bound to the peptide-binding groove of an MHC molecule. This form of activation results in a highly regulated, specific response. Super antigens are an exception to this rule. Super antigens are capable of cross-linking MHC molecules with families of T-cell receptors, inducing the activation of large numbers of T cells at once. This cross-linking does not require antigen processing and presentation by innate immune cells; consequently, super antigen–mediated diseases can present with a rapidly fulminating course. Such is the case for toxic shock syndrome, which is caused by staphylococcal or streptococcal bacterial toxins functioning as super antigens. Because the signs and symptoms—and much of the morbidity—of toxic shock syndrome are toxin mediated, antibiotic regimens generally include the addition of clindamycin to decrease toxin production. The addition of intravenous immunoglobulin (IVIG) to deliver toxin-neutralizing antibodies may also be of benefit, with observational studies demonstrating associations between IVIG use and decreased mortality in patients with toxic shock syndrome and other severe invasive group A streptococcal infections. ,


T-cell activation requires a second signal


As an additional layer of regulation, T-cell activation requires APCs to deliver two signals ( Fig. 101.3 ). The first is the antigen-specific T-cell receptor (TCR)/MHC interaction. The second signal is the antigen-nonspecific costimulatory signal provided by the interaction between costimulatory molecules expressed on APCs and receptors expressed by the T cell. If a T cell receives only antigen-specific TCR stimulation in the absence of costimulation, it will be rendered unresponsive to subsequent antigenic challenge. This process, which creates anergic T cells, is an important peripheral mechanism to promote T-cell tolerance to self-antigens. Costimulatory pathways can provide either positive signals that promote T-cell proliferation and differentiation or negative signals that inhibit T-cell responses and further mediate T-cell tolerance. As such, these pathways provide critical immunoregulatory function.


May 20, 2021 | Posted by in RHEUMATOLOGY | Comments Off on Adaptive immunity
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