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Chapter 41 Neuroimmunology

The past decade has seen a rich interaction between the fields of neurology and immunology. This has provided further insight into the mechanisms of immunologically-mediated neurological diseases and given rise to new therapies for many neuroimmunological diseases, including multiple sclerosis (MS). To understand and effectively employ these emerging neuroimmunologically based therapies, a solid grasp of immunology is required. Here we provide an overview of the major components of the immune system and highlight important advances in the field of neuroimmunology, with a focus on relevant disease processes and treatment strategies.

Immune System

The function of the immune system is to protect the organism against infectious agents and prevent reinfection by maintaining immunological memory. Additionally, the immune system performs tumor surveillance, promotes healing, and prevents damage mediated by dying cells.

The immune system normally does not react to self-antigens, a state known as tolerance, except in the setting of autoimmune disease. An overactive immune system may mediate ongoing immune-mediated damage, so a delicate balance must be maintained between the protective effects of the immune system and potential deleterious effects.

The normal functions of the immune system and the disorders resulting from its dysfunction are listed in Box 41.1.

Adaptive and Innate Immunity

The immune system has two functional divisions: the innate immune system and the adaptive immune system. The innate immune system acts nonspecifically as the body’s first line of defense against pathogens. However, this type of response, if perpetuated, would result in unwanted nonspecific damage to the host. Therefore a secondary, antigen-specific response develops and leads the attack. This is mediated by T cells and B cells, which are equipped with antigen-specific receptors. The effector cells release mediators and trigger other components of the immune system to eliminate the target. Subpopulations of T and B cells develop and maintain immunological memory, which facilitates a more rapid response in the case of recurrent infection.

The innate immune system consists of the following components:

1. Skin—The exterior surface of the body, primarily the skin, is the body’s primary defense against foreign pathogens. Many inflammatory cells and antigen-presenting cells (APCs) line the epidermis and serve as the first line of defense.

2. Phagocytes are cells capable of phagocytosing foreign pathogens. They include polymorphonuclear cells, monocytes, and macrophages. These cells are present in the blood as well as in organs. Phagocytes recognize cell components or pathogen-associated molecular patterns (PAMPs) of a variety of microorganisms through families of pattern recognition receptors (PRRs) expressed on their cell surface. PRRs allow phagocytes to attach nonspecifically and phagocytose pathogens, which are then killed via intracellular lysosomes. Families of PRRs include the Toll-like receptors (TLRs) and the nucleotide-binding oligomerization domain (NOD) receptors.

3. Natural killer (NK) cells—NK cells recognize cell surface molecules on virally infected or tumor cells. They subsequently bind to the infected cells and kill them via cell-mediated cytotoxicity.

4. Acute-phase proteins—C-reactive protein is a model acute-phase protein whose concentration increases in response to infection. C-reactive protein binds to cell surface molecules on a variety of bacteria and fungi and acts as an opsonin, essentially increasing recognition of pathogens by phagocytic cells.

5. Complement system—The complement system is a cascade of serum proteins whose overall function is to enhance and mediate inflammation. The complement system has the intrinsic ability to lyse the cell membranes of many cells including bacteria. It functions in concert with components of both the innate and adaptive immune systems and can also act as an opsonin, facilitating phagocytosis. The complement cascade can be directly activated by certain microorganisms through the alternative pathway, or it can be activated by particular antibody subtypes through the classical pathway.

The adaptive immune response consists of the following components:

1. Antibodies—Otherwise known as immunoglobulins (Igs), antibodies are able to specifically recognize a variety of free antigens. Igs are produced by B cells and are present on their cell surface. In addition, Igs are secreted in large amounts in the serum. Antibodies recognize specific microbial and other antigens through their antigen-binding sites and bind phagocytes via their Fc receptors, thereby facilitating antigen removal. Some subclasses of Ig are capable of activating complement via their Fc portion, thereby lysing their targets.

2. B cells—The primary function of B cells is to produce antibody. Antigen binding to B cells stimulates proliferation and maturation of that particular B cell, with subsequent enhancement of antigen-specific antibody production, resulting in the development of antibody-secreting plasma cells. Most B cells express class II major histocompatibility complex (MHC) antigens and have the ability to function as APCs.

3. T cells, or thymus-derived cells, have the ability to recognize specific antigens via their T-cell receptors (TCRs). T cells may be classified into two main groups, T-helper (TH) cells expressing CD4 antigen on their cell surface and T-cytotoxic (TC) cells expressing CD8 on their surface. CD4 T cells recognize antigen presented in association with MHC class II on the surface of APCs. CD4 T cells help to promote B-cell maturation and antibody production and produce factors called cytokines to enhance the innate or nonspecific immune response. CD8 T cells recognize antigen in association with MHC class I antigen on the surface of most cells and play an important role in eliminating virus-infected cells. Cytotoxic T cells are capable of damaging target cells via the release of degrading enzymes and cytokines. Responses in which the T cell plays a major role are termed cell-mediated immunity (CMI). T cell–macrophage interactions often lead to delayed reactions, termed delayed-type hypersensitivity (DTH).

4. APCs are required to present antigen to T cells. They are found primarily in the skin, lymph nodes, spleen, and thymus. Unlike B cells that can recognize free antigen, T cells are only capable of recognizing antigen in the context of self-MHC molecules. APCs process antigen intracellularly and present antigen peptide in the groove of their MHC class II molecules. The primary APCs are macrophages, monocytes, dendritic cells, and Langerhans cells.

Principal Components of the Immune System

Cells of the immune system arise from the pluripotent stem cells in the bone marrow and diverge into the lymphoid or myeloid lineages. The myeloid lineage primarily contains cells with phagocytic functions such as neutrophils, basophils, eosinophils, and macrophages. The lymphoid lineage consists of T cells, B cells, and NK cells.

T-Cell Receptors

The TCR consists of two glycosylated polypeptide chains, alpha (α) and beta (β), of 45,000 and 40,000 dalton molecular weight, respectively. This heterodimer of an α and β chain is linked by disulfide bonds. Amino acid sequences show that each chain consists of variable (V), joining (J), and constant (C) regions closely resembling Igs (Fig. 41.1). There are about 102 TCR-variable genes grouped by homology into a small number of families, compared with 103 or greater for Igs (see later discussion). The principles governing generation of diversity in the TCR are very similar to those for Ig genes. T cells can only recognize short peptides that are associated with MHC molecules. In contrast, the Ig receptor can recognize peptides, whole proteins, nucleic acids, lipids, and small chemicals.

T cells also express a variety of nonpolymorphic antigens on their surfaces. The most abundantly expressed is CD45, comprising 10% of lymphocyte membrane proteins. CD45 exists as a number of isoforms that differ in the molecular weight of their extracellular domains as a result of RNA splicing. These isoforms can be distinguished serologically. The low molecular weight (CD45RO) isoforms define activated, or memory, T-cell populations.


Immunoglobulins are glycoproteins that are the secretory product of plasma cells. Their biochemical structure and genomic organization is shown in Fig. 41.1. All Ig molecules share a number of common features. Each molecule consists of two identical polypeptide light chains (kappa [κ] or lambda [λ]) linked to two identical heavy chains. The light and heavy chains are stabilized by intrachain and interchain disulfide bonds. According to the biochemical nature of the heavy chain, Igs are divided into five main classes: IgM, IgD, IgG, IgA, and IgE. These may be further divided into subclasses depending on differences in the heavy chain.

Each heavy and light chain consists of variable and constant regions. The amino terminus is characterized by sequence variability in both the light and the heavy chain, and each variable heavy- and light-chain unit acts as the antigen-binding site (the Fab portion). The carboxy terminal of the heavy chain (also known as the Fc portion) is involved in binding to host tissue and fixing complement. This part of the molecule is important for antibody-dependent, cell-mediated cytotoxicity by cells of the reticuloendothelial system and for complement-mediated cell lysis.

Classes of Igs differ in their ability to fix complement. In humans, IgM, IgG1, and IgG3 antibodies are capable of activating the complement cascade. Different Ig classes also differ in their transport properties and ability to bind to phagocytes. Fc binding to Fc receptors (FcR) present on macrophages, dendritic cells, neutrophils, NK cells, and B cells initiates signaling within the cell only when the receptors are cross-linked by immune complexes containing more than one IgG molecule. Different Fc receptors (FcR) mediate different cellular responses, some being predominantly stimulatory, while others are inhibitory.

Genetics of the Immune System

Major Histocompatibility and Human Leukocyte Antigens

Major histocompatibility complex gene products or the human leukocyte antigens (HLAs) serve to distinguish self from nonself. In addition, they serve the important function of presenting antigen to the appropriate cells. The MHC class I gene product contains an MHC-encoded α chain, and a smaller non-MHC-encoded β2-microglobulin chain. The MHC class II gene product consists of two polypeptide chains, α and β, which are noncovalently linked. Both class I and class II proteins are stabilized by intrachain disulfide bonds. Class I antigens are expressed on all nucleated cells, whereas class II antigens are constitutively expressed only on dendritic cells, macrophages, and B cells and are also expressed on a variety of activated cells including T cells, endothelial cells, and astrocytes.

In humans, class I molecules are HLA-A, B, and C, whereas the class II molecules are HLA-DP, DQ, and DR. Several alleles are recognized for each locus; thus the HLA-A locus has at least 20 alleles, and HLA-B has at least 40. The number of alleles for the D region appears to be as extensive as that for HLA-A, HLA-B, and HLA-C. In view of the extensive polymorphisms present, the chances of two unrelated individuals sharing identical HLA antigens are extremely low. The reason for the extensive diversity and evolutionary pressure that lead to this are not fully understood.

Class I antigens regulate the specificity of cytotoxic CD8+ T cells, which are responsible for killing cells bearing viral antigens or foreign transplantation antigens (Fig. 41.2). The target cells share class I MHC genes with the cytotoxic cell. Thus the cytotoxic cell that is specific for a particular virus is capable of recognizing the antigenic determinants of the virus only in association with a particular MHC class I gene product. The function of class II MHC gene products appears to be to regulate the specificity of T-helper cells, which in turn regulate DTH and antibody response to foreign antigens. Similarly, an immunized T-cell population will recognize a foreign antigen only if it is presented on the surface of an APC that shares the same class II MHC antigen specificity as the immunized T-cell population. Thus the functional specificity of the T-cell population is restricted by the MHC molecules they recognize. CD8+ T cells (cytotoxic) and CD4+ T cells (helper) are referred to as MHC class I and MHC class II restricted T cells, respectively (Fig. 41.3).

The analysis of the three-dimensional structure of the class I and class II molecules has confirmed the notion that these molecules are carriers of immunogenic peptides that are processed by APCs and presented on the cell surface (Fig. 41.4). Both MHC class I and class II molecules share similarities in crystal structure that allow them to accept and retain immunogenic peptides in grooves, or pockets, and present them to T cells.

Organization of the Immune Response

Initiation of the Immune Response

Accessory Molecules for T-Cell Activation

The interaction of MHC-peptide complex with T cells, although necessary, is insufficient for T-cell activation. Other classes of molecules are involved in T-cell antigen recognition, activation, intracellular signaling, adhesion, and trafficking of T cells to their target organs. The distinction between the functions of these classes of molecules is not absolute, and many may be involved in interactions between other cells of the immune system.

Costimulatory Molecules

Costimulatory molecules serve as a “second signal” to facilitate T-cell activation. Costimulatory pathways that are critical for T-cell activation include the B7-CD28 and CD40-CD154 pathways. Members of the integrin families including vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule (ICAM-1), and leukocyte function antigen 3 (LFA-3) can provide costimulatory signals, but they also play critical roles in T-cell adhesion, facilitate interaction with the APCs, mediate adhesion to nonhematopoietic cells such as endothelial cells, and guide cell traffic (Fig. 41.5).

The B7-CD28 interaction is one of the most extensively studied costimulatory systems. The B7 molecules are expressed on antigen-presenting cells, and their expression is induced in activated cells. There are two forms of B7, B7-1 (CD80) and B7-2 (CD86), that share some homology but have different expression kinetics. The B7 molecules interact with their ligand, CD28, which is constitutively expressed on most T cells. Binding of the CD28 molecule mediates intracytoplasmic signals that increase expression of the growth factor, IL-2, and enhance expression of the anti-apoptotic molecule, Bcl-xL. An alternate ligand for B7 is CTLA-4, which is homologous to CD28 in structure, but in contrast to CD28, CTLA-4 functions to inhibit T-cell activation. Costimulatory molecules may deliver either a stimulatory (positive) or inhibitory (negative) signal for T-cell activation (Brunet et al., 1987). Examples of molecules delivering a positive costimulatory signal for T-cell activation include the B7-CD28, CD40-CD154 pathways. Examples of molecular pathways delivering a negative signal for T-cell activation include B7-CTLA4 and PD1-PD ligand (Khoury and Sayegh, 2004). The delicate balance between positive and negative regulatory signals can determine the outcome of a specific immune response.

Accessory Molecules for B-Cell Activation

Like T cells, B cells require accessory molecules that supplement signals mediated through cell-surface Igs. Signaling molecules whose functions are likely to be analogous to CD3 are linked to Ig. Unlike T cells that may only respond to peptide antigens, B cells can respond to proteins, peptides, polysaccharides, nucleic acids, lipids, and small chemicals. B cells responding to peptide antigens are dependent on T-cell help for proliferation and differentiation, and these antigens are termed thymus-dependent (T-dependent). Nonprotein antigens do not require T-cell help to induce antibody production and are therefore T-independent.

The interaction between B cells and T-helper (CD4+) cells requires expression of MHC class II by B cells and is antigen dependent. In addition, a number of other molecules mediate adhesion between T and B cells and induce signaling for B-cell activation. These include B7 expressed on B cells interacting with CD28 on T cells and CD40 on B cells interacting with CD154. Interaction of T-helper and B cells occurs in the peripheral lymphoid organs, initially in the primary follicles and later in the germinal centers of the follicle. Activation of B cells induces activation of transcription factors (c-Fos, JunB, NFκB, and c-Myc), which in turn promote proliferation and Ig secretion. Cytokines elicited from the T-helper cell induce isotype switching in B cells, producing stronger and long-lived memory responses, in contrast to weak IgM responses to T-independent antigens.

Further generation of high-affinity antibody-producing B cells and memory B cells occurs in the germinal center of lymphoid follicles through a process called affinity maturation. As the amount of available antigen lessens, B cells that do not express high-affinity receptors for antigen are eliminated by apoptosis. Some B cells lose the ability to produce Ig but survive for long periods and become memory B cells.

Regulation of the Immune Response


Cytokines play a major role in regulating the immune response. Cytokines are broadly divided into the following categories, which are not mutually exclusive: (1) growth factors: IL-1, IL-2, IL-3, and IL-4 and colony-stimulating factors; (2) activation factors, such as interferons (α, β, and γ, which are also antiviral); (3) regulatory or cytotoxic factors, including IL-10, IL-12, transforming growth factor beta (TGF-β), lymphotoxins, and tumor necrosis factor alpha (TNF-α); and (4) chemokines that are chemotactic inflammatory factors, such as IL-8, MIP-1α, and MIP-1β.

Cytokines are necessary for T-cell activation and for the amplification and modulation of the immune response. A limited representation of the cytokines that participate in the immune response is shown in Table 41.1. Secretion of IL-1 by macrophages results in stimulation of T cells. This leads to synthesis of IL-2 and IL-2 receptors and finally to the clonal expansion of T cells. Only activated T cells express the IL-2 receptor (CD25); therefore the cytokine-induced expansion favors antigen-activated cells only. T-cell activation causes secretion of interferon gamma (IFN-γ), which induces expression of MHC class I and class II molecules on many cell types including APCs. This in turn increases the T-cell response to the antigen. Secretion of IL-2 also results in activation of NK cells that mediate lysis of tumor cell targets. In addition, IL-3 is released, resulting in stimulation of hematopoietic stem cells. The signal for differentiation of B cells to form antibody-secreting cells involves clonal expansion and differentiation of virgin memory B cells. IL-4 and B-cell differentiation factors secreted by T cells induce differentiation and expansion of committed B cells to become plasma cells.

IFN-α and IFN-β are both type I interferons. IFN-α is produced by macrophages, whereas IFN-β is produced by fibroblasts. Both inhibit viral replication by causing cells to synthesize enzymes that interfere with viral replication. They also can inhibit the proliferation of lymphocytes by unknown mechanisms.

Although the emphasis has been on factors that cause expansion and differentiation of lymphocytes, there are cytokines that can down-regulate immune responses. Thus IFN-α and IFN-β, in addition to possessing antiviral properties, can modulate antibody response by virtue of their antiproliferative properties. Similarly, TGF-β (a cytokine produced by T cells and macrophages) can also decrease cell proliferation. IL-10, a growth factor for B cells, inhibits the production of IFN-γ and thus may have antiinflammatory effects.

CD4+ T-helper cells differentiate into TH1 or TH2 phenotypes, as well as a recently described TH17 subset, which secrete characteristic cytokines and stimulate specific functions. TH1 cells secrete IFN-γ, IL-2, and TNF-α. These cytokines exert proinflammatory functions and, in TH1-mediated diseases such as MS, promote tissue injury. IL-2, TNF-α, and IFN-γ mediate activation of macrophages and induce DTH. TH1 cell differentiation is driven by IL-12, a cytokine produced by monocytes and macrophages. In contrast, the TH2 cytokines IL-4, IL-5, IL-6, IL-10, and IL-13 promote antibody production by B cells, enhance eosinophil functions, and generally suppress cell-mediated immunity (CMI). TH3 cells secrete TGF-β, which inhibits proliferation of T cells and inhibits activation of macrophages. Cytokines of the TH1 type may inhibit production of TH2 cytokines and vice versa. More recently, a subset of T cells that predominantly produce IL-17 have been described (Yao et al., 1995). These cells are believed to represent a distinct subset from IFN-γ-producing TH1 cells, evidenced by the dependence of THIL-17 cells on IL-6 and TGF-β for differentiation (Bettelli et al., 2006; Mangan et al., 2006; Veldhoen et al., 2006) and IL-23 for expansion (Aggarwal et al., 2003; Langrish et al., 2005), as opposed to TH1 cells, which are dependent on IL-12 and IL-2, respectively, for differentiation and expansion. Both TH1 and TH2 cytokines have been shown to suppress the development of TH17 cells (Harrington et al., 2005; Park et al., 2005). THIL-17 cells facilitate the recruitment of neutrophils and participate in the response to gram-negative organisms. These cells may also play a role in the initiation of autoimmune disease. Another effector T-cell subset, TH9 cells, has recently been described (Dardalhon et al., 2008; Veldhoen et al., 2008). Driven by the combined effects of TGF-β and IL-4, TH9 cells produce large amounts of IL-9 and IL-10. It has been shown that IL-9 combined with TGF-β can contribute to TH17 cell differentiation, and TH17 cells themselves can produce IL-9 (Elyaman et al., 2009).

Traditionally, TH cell subsets have been distinguished by their patterns of cytokine production, but identification of distinguishing surface molecule markers has been a major advance in the field. Tim (T cell, immunoglobulin and mucin-domain containing molecules) represent an important family of molecules that encode cell-surface receptors involved in the regulation of TH1 and TH2 cell–mediated immunity. Tim-3 is specifically expressed on TH1 cells and negatively regulates TH1 responses through interaction with the Tim-3 ligand, galactin-9, also expressed on CD4+ T cells (Monney et al., 2002; Sabatos et al., 2003; Zhu et al., 2005). Tim-2 is expressed on TH2 cells (Chakravarti et al., 2005), and appears to negatively regulate TH2 cell proliferation, although this has not been fully established. Tim-1 is expressed on TH2 cells > TH1 cells, and interacts with Tim-4 on APCs to induce T-cell proliferation (Meyers et al., 2005).

Termination of an Immune Response

The primary goal of the immune response is to protect the organism from infectious agents and generate memory T- and B-cell responses that provide accelerated and high-avidity secondary responses on reencountering antigens. It is desirable to terminate these responses once an antigen has been cleared. In parallel, the immune system must constantly function to prevent autoimmune activation and maintain self-tolerance. A number of systems operate to prevent uncontrolled responses. Here we discuss termination of individual components of the immune response. Following is a discussion of the mechanisms that maintain self-tolerance, many of which are also involved in immune-response termination.


An organism’s ability to maintain a state of unresponsiveness to its own antigens is termed self-tolerance. Self-tolerance is maintained through three principal mechanisms: deletion, anergy, and suppression. Self-tolerance may be broadly categorized as either central or peripheral tolerance. Similar mechanisms may also be used to induce tolerance to a foreign antigen or terminate an immune response.

Peripheral Tolerance

Self-reactive lymphocytes may escape central tolerance; therefore peripheral mechanisms exist to maintain self-tolerance. This is termed peripheral tolerance. Peripheral tolerance is maintained through clonal anergy or clonal deletion. It is not clear to what extent each of these mechanisms functions in maintaining human self-tolerance; however, extensive research has been done to elucidate the mechanisms through which anergy and deletion work. In addition, self-tolerance may be maintained despite the presence of antigen-responsive lymphocytes. It is postulated that this is due to the presence of suppressor T cells or other factors that may interfere with a successful lymphocyte response.

Anergy Due to Failure of T-cell Activation

In normal circumstances, an APC presents antigen as a peptide + MHC complex (signal one). In the absence of signal one, the T cell dies because of neglect. If signal one is presented in the absence of costimulatory signals (signal two), the T cell becomes anergic. An example of this situation occurs when an antigen is presented by nonprofessional APCs that lack the appropriate costimulatory molecules (Fig. 41.6). However, when a T cell is activated, it up-regulates the expression of an alternate costimulatory molecule, CTLA-4. CTLA4 engagement by CD80 and CD86 on the surface of APCs sends a negative signal to the T cell, inhibiting cell growth and proliferation. Animals deficient for CTLA-4 expression on their T lymphocytes have an uncontrolled lymphoproliferative phenotype with autoreactivity (Waterhouse et al., 1995).