Back to Basics (1997)

The need to understand basic principles of immune function has become increasingly relevant to pediatricians as the immunopathogenesis of a large variety of human diseases has been elucidated. The central role of the immune system in many diseases coupled with the worldwide pandemic of the human immunodeficiency virus (HIV) infection has moved immunology into the forefront of clinical medicine. The purpose of this review is to develop the basic principles that govern the cellular network of the human immune system as it protects the host against a vast array of foreign pathogens.These defenses consist first of a phylogenetically more primitive innate system that is provided primarily by phagocytic cells and acts as a first-line defense against many bacterial pathogens. The complement system amplifies the innate immune response by providing critical factors that enhance phagocytosis (opsonins) and attract cells to the site of inflammation(chemoattractants). The more recently acquired defense pathway, the adaptive immune system, involves a highly specific immune response to foreign substances (antigens) that includes lymphocytes. This chain of events is initiated by lymphocyte binding antigen and consists of cell-cell interactions and the release of numerous humoral mediators,including immunoglobulins and potent bioactive hormones called cytokines.The division of labor within these various arms of the immune system is carried out by specific cell types. The two primary players are neutrophils and macrophages. Neutrophils are mobile phagocytes that migrate to sites of inflammation where they ingest and destroy microorganisms. The macrophage is a fixed tissue cell, found throughout the lymphoid and mucosal tissues, that provides critical phagocytic function for clearing antigenic substances from the circulation. The ingestion of foreign antigens by both cell types is enhanced in the presence of antibody and complement bound to the antigen.The adaptive immune system is controlled by various lymphocyte subpopulations. The T cells are the most numerous lymphocytes in the circulation (∼75%) and provide regulatory, memory, and cytotoxic effector (killer) cells. Collectively,the T cells are referred to as the cellular immune system. The less numerous B cells (∼10% to 15%)secrete antibodies or immunoglobulins and are referred to as the humoral immune system. A third type of lymphocyte, called the natural killer (NK) cell, acts as a specific type of cytotoxic cell,but its role in host defense is less well defined.As noted previously, the innate immune system consists of phagocytic cells and the complement system. Within the cellular constituents,the neutrophil is a prototypic cell in the host defense that can respond rapidly to an infection. Neutrophils are capable of directed movement to the source of infection and upon arrival are programmed to engulf(via phagocytosis) and destroy the infecting organism. This process depends on certain surface receptors that recognize components of bacterial cell walls as well as serum proteins bound to the microorganism. In addition, phagocytosis is enhanced markedly by the presence of specific antibodies and complement on the surface of the antigen (organism). These humoral factors act as a bridge between the microbe and the phagocytic cell. The phagocytic process internalizes the organism into an intracellular compartment(phagolysosome). This engulfing action is followed by the release of intracellular products, including toxic oxygen metabolites, proteases,phospholipases, and defensins,that kill both Gram-negative and Gram-positive organisms as well as many fungi. As expected,neutrophil deficiencies are associated with recurrent bacterial and fungal infections.A new class of low-molecular-weight cytokine mediators has been identified that both attracts and activates neutrophils and activates selected lymphocyte functions. These polypeptides are called chemokines and play a significant role in mediating the inflammatory response. In addition, certain of the receptors for chemokines recently have been shown to serve as the coreceptor for HIV entry (infection)into the CD4 T cell. These findings may lead to new strategies for the therapy of HIV infection.The complement system amplifies the innate immune response;it consists of a number of serum proteins that, upon stimulation,initiate the sequential activation of the complement cascade. Two major pathways can initiate the complement cascade, each involving separate but analogous protein components that converge in a final common pathway. This activation generates opsonic activity, bioactive substances, and an active membrane lysing (attack) complex (Fig. 1). The phylogenetically older alternative pathway is activated through interaction with the membranes of pathogens such as Gram-negative organisms. In contrast, the classical pathway requires the adaptive immune system because it is activated by a complex of specific antibody (immunoglobulin G [IgG]or IgM) bound to an antigen(eg, bacteria).Both paths of activation generate bioactive substances that mediate inflammation, including chemoattractants and anaphylatoxins. The former draw neutrophils to the site of inflammation; the latter increase vascular permeability and induce smooth muscle contraction, helping increase the delivery of inflammatory cells and mediators. The major opsonic activity of complement is generated by both pathways via the activation and binding of a specific complement component, C3, to the surface of a microbe, which serves as a bridge between the microbe and the phagocytic cells. Activation of the final (terminal) components in the complement cascade generates a group of components referred to as the membrane-attack complex. This complex generates a pore in the cell membrane that allows for free exchange of intracellular and extracellular contents to kill selected pathogens directly.Clinical disorders affecting the innate immune system most commonly are the result of neutropenia caused either by disease or by therapy (eg, chemotherapy). Patients who have neutropenia typically present with serious bacterial or fungal infections that involve the skin, lung, liver, bone, and oral cavity. In addition, less common congenital abnormalities of neutrophil function (eg, chronic granulomatous disease, leukocyte adhesion deficiency) have helped to define the crucial roles of neutrophil adhesion,migration, and killing in the normal host response to bacteria and fungi.Deficiency of the complement component C3 is associated with the same clinical consequences as antibody deficiencies, resulting in recurrent sinopulmonary infections due to encapsulated bacteria. This pathologic effect emphasizes the crucial role that C3 plays as an opsonin for the normal elimination of organisms such as Haemophilus influenzae and Streptococcus pneumoniae. Disorders in one of the terminal complement components (membrane attack complex) are associated with recurrent Neisseria sp infections. This clinical consequence identifies the membrane attack complex as having a special role in elimination of these bacteria. Finally, early complement component deficiencies are associated with an increased incidence of autoimmunity.The more recently acquired network in the host defense, the adaptive immune system, is regulated by lymphocytes and has developed as an antigen-specific response. This capability requires a vast array of receptors that are matched to different individual antigens. Such a specific interaction is accomplished by the T cell through the expression of a T cell antigen receptor (TcR) on its surface and by the B cell through an antibody (immunoglobulin)molecule on its surface. These receptors(TcR and immunoglobulin) enable the adaptive immune system to act in an antigen-specific fashion. The genetic process required for the generation of these receptors is unique and involves rearrangement between individual elements found in specific regions of the TcR or immunoglobulin genes (referred to as variable [V], diversity [D],and joining [J] regions).The principle of this process is similar to constructing a hand of cards, using one genetic element(“card”) from each of the different(V, D, and J) regions (“decks”). Because of the large number of elements (“cards”) in these three regions (“decks”) and some other genetic events that increase diversity, it has been estimated that 1012or more specific receptors can be generated for each cell type. This process is random, occurs early in the development of T cells and B cells, and produces the vast array of unique specificities (“hands”)that provide a specific receptor for virtually any antigen. Once a specific surface receptor (TcR or immunoglobulin) is expressed, it is the only antigen recognition structure that this individual cell and its progeny ever will express or, in the case of immunoglobulins, secrete. Thus, massive numbers of different lymphocytes (T cells and B cells),each expressing different receptors,are required to ensure a match for any antigen that might be encountered during an individual’s lifetime.Despite the genetic similarity in the process that is used to generate antigenic diversity in T cells and B cells, the interactions between an antigen and these two cell receptors are fundamentally different. The T cell recognizes only a small peptide fragment that is derived from the whole protein antigen, while the B cell interacts with the whole(soluble) antigen. This difference is based on the inability of the TcR to recognize whole antigen. Rather, this receptor can bind only to an antigenic fragment (ranging from 8 to more than 20 amino acids) bound and displayed on a human leukocyte antigen (HLA) molecule that is found on the presenting cell surface. These HLA molecules originally were identified as human transplantation antigens, but they now are known to have a fundamental role in immune recognition through the display (presentation) of antigenic fragments to T cells. Certain HLA molecules (HLA-A, -B, -C) are found on virtually all nucleated cells; others (HLA-DR, -DP, -DQ)are restricted to certain cell types(antigen-presenting cells: monocytes,dendritic cells, B cells).The antigenic fragments recognized by T cells are derived from two different sources. One is an endogenous antigenic pool found within the cell. This pool includes viral antigens, which are produced after a virus infects a cell, inserts its genetic code into the host’s DNA,and induces the synthesis of viral proteins (antigens). Fragments of these viral proteins are displayed by HLA molecules on the surface of the infected cell, and these foreign antigens alert the T cell system to the viral infection. The alternative type of antigenic fragments is generated from exogenous antigens such as bacteria. The presentation of these requires phagocytosis of the antigen by specialized cells(antigen-presenting cells), cleavage of the protein (eg, bacterial)antigens, and display of the antigenic fragment on the cell surface (HLA molecules). The immune system recognizes the difference between endogenous and exogenous antigenic fragments at the level of the T cell interaction with antigen. CD8 T cells recognize endogenous antigenic fragments, and CD4 T cells recognize exogenous antigenic fragments. There are additional restrictions involved in this process at the level of the HLA molecules displaying the antigenic fragments, but that is beyond the scope of this presentation.CD4 T cells have a central role in the immune network, based on their function as helper and regulatory cells. These effects are accomplished by direct cell-cell interactions and through the secretion of a large number of regulatory cytokines. The hormone mediators affect multiple immune cell functions and in general terms can be categorized as: 1) immune regulator-lymphocyte growth factor (eg,interleukin [IL]-2, IL-4), 2) inflammation inducer (eg, interferon-gamma, IL-5,IL-10, IL-12), and 3) bone marrow stimulator (eg, IL-3, granulocyte macrophage-colony stimulating factor [GM-CSF]) cytokines. This overly simplified division of labor fails to recognize that all cytokines have multiple and often overlapping functions that may fall into more than one category.An additional property of CD4 T cells is the generation of memory cells following the initial encounter with an antigen. This unique feature of the adaptive immune system provides for a more rapid and heightened immune response that represents the underlying foundation for successful immunizations.Results of recent studies have suggested a model of CD4 T helper cell function that involves at least three different functional helper T cell types: TH0, TH1, TH2. In this paradigm, the TH0 cells are the source of the functional helper cells, the TH1 and TH2 cells(Fig. 2). A TH1 response results in delayed type hypersensitivity inflammation that involves monocytes and neutrophils as well as the generation of cytotoxic (CD8) T cells. A TH1 response is characterized by the production of interferon-gamma,IL-12, and other cytokines.In contrast, a TH2 response specifically generates IL-4, IL-5,and IL-10 cytokines that increase IgE production and mediate eosinophil recruitment and activation. Recent data confirm that an active TH2 response inhibits a TH1 response and vice versa.Development of this paradigm has led to experimental therapies for selected immune disorders that both employ selected cytokines and block specific cytokines or their receptors. An example of this strategy is the addition of interferon-gamma when standard antibiotic therapy proves inadequate for disseminated Mycobacterium avium intracellularecomplex infection in nonHIV-infected patients. This adjunctive cytokine therapy has resulted in significant clinical improvement in some patients and suggests that modulating specific lymphocyte pathways may be beneficial in the treatment of selected infections and perhaps other disorders.The mechanisms controlling T-cell differentiation into TH1 or TH2 helper cells are not fully understood, although host genetic factors are involved. Other likely influences include the type of antigen (eg, bacteria-TH1, parasite-TH2)inducing the response, the route of antigen exposure (eg, parenteral,mucosal), the cells involved at the time of the initial reaction, and the cytokine exposure at the local environment.The familial nature of allergic disease suggests that the type of T helper cell response induced by allergens is under genetic control. Atopic individuals respond to inhaled allergen by producing IgE and mounting local eosinophilic inflammation (TH2); nonatopic individuals have no IgE and little or no local inflammation (TH1). Similarly, certain types of microorganisms (eg, parasites) appear to favor a TH2 immune response,while others (eg, Mycobacterium sp)appear to induce a TH1 response. As noted previously, multiple factors probably play a role in determining the type of T helper response generated. Further clarification of these mechanisms should provide a framework for understanding the immunopathogenesis of various immunologic/inflammatory diseases and stimulate new approaches for immunomodulatory therapy.CD8 T cells function primarily as cytotoxic (killer) cells and as such can interact with virtually any nucleated host cell that expresses an endogenously derived antigen(eg, virus-infected cell expressing viral antigens as peptide fragments bound to HLA molecules). This capability means that the CD8 T cell can mount a cytotoxic response in response to a viral infection involving any tissue, a clear advantage in terms of host defense. In addition to their cytotoxic effector function,CD8 T cells also secrete cytokines that can modulate immune reactions and may have a role in negatively regulating (suppressing) immune responses.An immune response to foreign(nonself) antigens and nonresponse to self antigens is critical for host protection without the occurrence of autoimmunity. This selectivity in the immune reaction depends on the deletion of autoreactive lymphocytes during T cell development, which occurs primarily in the thymus. The environment of the thymus facilitates the elimination of T cells that react with self-antigens as well as T cells that fail to differentiate normally. Although this process is very effective, some autoreactive T cells are released into the circulation. These cells appear normally to be inactivated through various processes of peripheral T cell modification that include induction of specific T-cell unresponsiveness,alteration in the T-cell response pattern (ie, switching between TH1 and TH2 responses), generation of suppressor cells, and peripheral deletion of autoreactive cells.One current model for the peripheral modification (tolerance)of T cells is based on the known requirement for two different signals to activate T helper cells. The first signal is provided through TcR binding the antigenic fragment-HLA molecule complex. The second signal for activation is provided by specialized receptors and is referred to as a costimulatory signal (Fig. 3). Exposure of T cells to the first signal in the absence of the second induces a state of antigen-specific T-cell unresponsiveness (anergy). The unique surface molecules that provide the second signal are present on the specialized antigen-presenting cells (APC). In contrast,other normal (nonAPC) cells do not express these special surface molecules, but do express self-antigenic fragments (bound to HLA molecules on all cells). Therefore, a self-reactive lymphocyte encountering self-antigen on these normal (nonAPC)cells receives only one signal. The result is T-cell unresponsiveness for this self antigen (self-tolerance),which should protect against autoimmunity. This appears to represent one of many mechanisms for inducing peripheral tolerance to self-antigens. Gaining a clearer understanding of these pathways may help to clarify the changes that lead to autoimmune disease. This also should result in alternative and more specific approaches for the therapy of autoimmunity as well as the prevention of graft rejection following organ transplantation.The recognition that a TH1 response inhibits the development of a TH2 response and vice versa is based on the inhibitory effects that selected cytokines have on the alternative T helper response. This phenomenon suggests that alteration in the type of T helper cell could provide an approach for immune modulation. This mechanism appears to explain a successful response to allergen immunotherapy in which a TH2 (IgE and eosinophil)-mediated allergic response is suppressed by the switch to a TH1 response induced by the allergen-specific immunotherapy.The process of B-cell differentiation occurs primarily in the bone marrow where autoreactive B cells are eliminated during cell differentiation and remaining surface immunoglobulin-positive B cells are released into the circulation. The requirement for an intracellular signal in normal B-cell development has been revealed by the defect in an intracellular protein, Bruton tyrosine kinase (BTK), found in X-linked(Bruton) agammaglobulinemia. This genetic defect blocks B-cell differentiation in the bone marrow and results in both a lack of circulating B cells and an absent antibody response. Interestingly, other hematopoietic cells are not affected by the defect in BTK.The antigen specificity of B cells depends on the cell surface immunoglobulin that is present on mature B cells as a combination of IgM and IgD. Both classes of antibody expressed on the cell surface have exactly the same antigen specificity(ie, antigen binding structure) for soluble antigen. For example,following immunization with tetanus toxoid, the injected antigen binds only to B cells that express surface immunoglobulin specific for tetanus toxoid. The binding of antigen represents the first step in the initiation of the final differentiation of a B cell into a plasma cell. With the appropriate combination of signals and factors, the cell can switch its production to another class (IgG,IgA, or IgE), again with the same antigen specificity. However, this process requires a second signal provided by an activated CD4 T cell plus specific cytokines that are necessary for the actual class switch (eg, IL-4 for IgE) (Fig. 4). A primary immune deficiency, the X-linked form of the hyper-IgM syndrome, helped to elucidate the B-cell class switch process. The majority of these patients have a defect in the surface molecule,CD40 ligand, that normally is expressed on T cells following activation (Fig. 4). This molecule provides the cell-cell signal necessary for B cells to undergo class switch. Patients lacking this T-cell surface molecule cannot undergo immunoglobulin class switch and fail to produce IgG, IgA, or IgE following primary and secondary immunization.To summarize, within the adaptive immune network, the CD4 T cell provides regulatory effects that play a central role in controlling the majority of immune functions and memory cells that enhance host protection. Many of the regulatory effects are mediated through the release of cytokines, a group of hormones that also promotes inflammation and replenishes hematopoietic elements. The CD8 T cell functions as a cytotoxic cell that is a crucial part of the host defense against intracellular pathogens such as viruses. The other major arm of the lymphoid network consists of B cells whose major function is the production of immunoglobulins that are crucial in host protection against encapsulated bacteria and other microbes. The role of the NK cell is less clear, but it appears to participate in host defenses against selected viruses and malignant cells. It also may be important in rejection reactions that are activated following tissue transplantation. The various lymphocyte types within the adaptive immune system are interdependent, as evidenced by the X-linked hyper-IgM syndrome in which a T-cell deficiency (CD40 ligand) manifests clinically as an antibody production problem.Clinical lessons provided by immune deficiency diseases have helped to clarify the role of the lymphocyte subpopulations in host defense. Disorders affecting the cellular arm of the adaptive immune system demonstrate the crucial role that T cells play in the host defense against opportunistic organisms,including viruses (eg,cytomegalovirus) and fungi (eg, Candida albicans). A common clinical example of this type of immune defect is the devastating opportunistic infections that result from CD4 T cell dysfunction or depletion found in patients who have acquired immunodeficiency syndrome.Defects in the humoral immune system present clinically with recurrent pneumonias, sinusitis, and otitis media. Patients who have antibody deficiencies demonstrate that B-cell production of immunoglobulins is central in defending the sinopulmonary tract against encapsulated bacteria.The role of the third member of the lymphocyte network, the NK cell, in host protection remains less well-defined. A single patient who had no NK cells was reported to have difficulty dealing with the herpes group of viruses. As a group,the various lymphoid deficiencies demonstrate that a normal lymphoid system is crucial for host defenses against the multiple microorganisms present in the environment.The innate and the adaptive immune systems provide a rapid and specific means of protecting the host against a vast array of microbes. Furthermore, the immune system plays a central role in the pathogenesis of many disorders that involve an inflammatory response, including allergic and autoimmune diseases. New and more effective therapies for this wide range of disorders will develop as our understanding of the immune network and its many secreted mediators continues to increase.